Новые мишени в иммунотерапии рака

Burugu S, Dancsok AR, Nielsen TO. Emerging targets in cancer immunotherapy. Semin Cancer Biol. 2017 Oct 5. pii: S1044-579X(17)30182-7. doi: 10.1016/j.semcancer.2017.10.001.

---

Введение

Противоопухолевую иммунотерапию сейчас считают столпом противоопухолевого лечения наряду с хирургией, химио- и лучевой терапией. Ипилимумаб и ниволумаб/пембролизумаб принадлежат группе первых ингибиторов иммунных чекпоинтов (таргетирующих CTLA-4 и PD-1, соответственно) и теперь синтезированы ингибиторы второго поколения, предпочтительная терапия первой линии распространенного немелкоклеточного рака легкого и меланомы. Лечение с этими агентами может индуцировать резистентность через апрегуляцию дополнительных иммунных чекпоинтов, подчеркивая необходимость в новых противоопухолевых иммунно-активирующих агентах. Новые препараты таргетируют не только лимфоциты, ассоциированные с приобретенным иммунитетом через блокаду иммунно-ингибиторных чекпоинтов или как агонисты иммуностимулирующих путей, но также и врожденные иммунные процессы, опосредуемые макрофагами и естественными киллерными (NK) клетками, пути, широко релевантные для многих типов солидных карцином и гемобластозов (маркеры суммированы на рисунке 1). Последующие новые иммунные мишени для противораковой иммунотерапии были отобраны на основе более поздних стадий их доклинических/клинических исследований и на ограниченном количестве обзорных статей, описывающих некоторые из этих мишеней.

Фиг. 1. Обзор новых мишеней для противоопухолевой иммунотерапии. Иммунные ингибиторные взаимодействия маркированы красным, иммунные костимуляторные взаимодействия маркированы зеленым цветом.

Приобретенный иммунитет

Ингибиторные лимфоцитарные рецепторы

LAG-3

Lymphocyte Activation Gene 3 (LAG-3) — рецептор, экспрессируемый на поверхностни активированных Т клеток, маркер истощения с иммуносупрессорной активностью. Класс II главного комплекса гистосовместимости (MHC-II) является лигандом для LAG-3; дополнительные лиганды (например, L-селектин и галектин-3) также идентифицированы. Регуляторные Т клетки (Treg), экспрессирующие LAG-3, имеют повышенную супрессорную активность, тогда как цитотоксические CD8+ Т клетки, экспрессирующие LAG-3, показывают сниженные скорость пролиферации и продукцию эффекторных цитокинов в канцере и аутоиммунном диабете. Сплайсинговый вариант LAG-3, расщепляемый металлопротеиназами и секретируемый в клеточную микросреду, имеет иммунно активирующие свойства после связывания с MHC-II на антиген-представляющих клетках.

LAG-3+ опухоль-инфильтрирующие лимфоциты (TIL) описаны у пациентов с меланомой, канцером толстого кишечника, панкреаз, молочной железы, легкого, гематопоеза и головы и шеи, в сочетании с агрессивными клиническими чертами. Антитело-базисная блокада LAG-3 во множественных мышиных моделях рака восстанавливает CD8+ эффекторные Т-клетки и уменьшает популяции Treg, влияние, усиленное в сочетании с анти-PD-1. Недавнее изучение в мышиной модели метастатического рака яичника показывало, что блокада LAG-3 ведет к ап-регуляции других иммунных чекпоинтов (PD-1, CTLA-4 и TIM-3), и комбинированная терапия, таргетирующая LAG-3, PD-1 и CTLA-4 повышает уровни функциональных цитотоксических Т клеток, редуцируя Treg и супрессорные клетки миелоидного происхождения.

Множественные клинические исследования ранней фазы тестировали антагонистические LAG-3 агенты в комбинации с анти-PD-1 и/или анти-CTLA-4 терапией (Таблица 1). Ввиду активирующих свойств растворимого секретируемого LAG-3 растворимое агонистическое LAG-3 антитело (IMP321) было тестирование в распространенных солидных злокачественных опухолях как единичный агент [19] и продемонстрировало достаточную переносимость и эффективность с гарантией перехода ко II фазе.

TIM-3

T—cell Immunoglobulin— and Mucin—domain—containing molecule 3 (TIM-3) является иммунно-ингибиторной молекулой, первоначально идентифицированной на CD4+ Th1 (хелперных) Т-клетках и CD8+ Tc1 (цитотоксических) Т-клетках, и позже на Th17 Т-клетках, регуляторных Т клетках и клетках врожденного иммунитета. TIM-3 активируются, главным образом, его широко экспрессируемым лигандом, галектином-9, ведя к гибели эффекторных Т-клеткок путем поступления кальция в клетку, клеточной агрегации и апоптоза. Когда TIM-3 сигналинг активен, интерферон-продуцирующие Т-клетки становятся истощенными, ведя к супрессии Th1 и иммунной толерантности. Tim-3 экспрессия традиционно наблюдается во время хронической инфекции как характерный маркер истощенных Т клеток.

В канцере опухоль-инфильтрирующие лимфоциты, экспрессирующие TIM-3, описаны в меланоме, неходжкинской лимфоме, раке легкого, желудка и других карциномах. В этих изучениях Tim-3 cо-экспрессируется с PD-1 и ассоциируется с истощением и дисфункцией эффекторных Т-клеток. Этот феномен также наблюдается в мышиных моделях солидных карцином и гемобластозов, где Tim3+ PD1+ CD8+ Т-клетки показывают истощенный фенотип, характеризуемый редуцированной пролиферацией и дефектной продукцией IL-2, TNFα и IFN-γ. Напротив, TIM-3 позитивные Treg показывают повышенную экспрессию эффекторных молекул и более иммуносупрессорны, чем их TIM-3 негативные копии.

Ингибирование только одного TIM-3 слабо влияет на рост опухоли в доклинических мышиных моделях, несмотря на некоторое свидетельство, поддерживающее реверсирование истощения иммунных клеток. Однако, комбинированный таргетинг PD-1 и TIM-3 ведет к выраженному замедлению роста опухоли, больше, чем любой из этих путей в многочисленных, доклинических in vivo моделях, поддерживая концепцию, что злокачественные клетки становятся резистентными к блокаде PD-1 чекпоинта, активируя другой иммунный чекпоинт. Действительно, мышиные модели, частично отвечающие на ингибирование PD-L1, повышенно регулируют Tim-3 экспрессию в резистентных опухолях, и добавление блокады TIM-3 успешно преодолевает эту резистентность. Апрегуляция TIM-3 также наблюдалась у пациентов, получавших монотерапию PD-L1, предполагая, что это может представлять форму адаптивной резистентности к этой терапии. Четыре клинических исследования ранней фазы в стадии реализации, которые пытаются комбинировать анти-PD-L1 терапию с агентами, таргетирующими TIM-3 (Таблица 1).

TIGIT

Трансмембранный протеин TIGIT (T cell Immunoglobulin and ITIM domain) является рецептором, который действует как иммунный чекпоинт для T и NK клеток посредством двух иммунорецепторных тирозин-базисных ингибиторных последовательностей (immunoreceptor tyrosine-based inhibitory motifs , ITIM) в его цитоплазматическом хвосте. Существует два основных лиганда TIGIT (CD155 и CD112), преимущественно экспрессируемых на антиген-представляющих клетках, и однин недавно открытый лиганд, названный нектин-2. Иммуносупрессорные действия TIGIT, видимо, имитируют взаимодействия CTLA-4 с клеточно-поверхностным рецептором B7. Связывание CD155 с CD226 (рецептор на T и NK клетках) ведет к активации эффекторных функций, которые ингибируются, когда CD155 вместо этого связывается с TIGIT.

Мыши с дефицитом TIGIT сенситивны к аутоиммунному артриту. В канцере блокада TIGIT ведет к регрессии опухоли, повышенной выживаемости и устойчивости к опухолевому вызову в мышиных моделях меланомы и рака толстого кишечника. О высокой экспрессии TIGIT mRNA и высоких уровней TIGIT+ лимфоцитов проточной цитометрией сообщили в человеческой почечно-клеточной карциноме, меланоме, раке легкого, молочной железы и пищевода.

В меланоме NY-ESO-1-специфические TIGIT+ CD8+ Т клетки cо-экспрессируют другие маркеры иммунных чекпоинтов, такие как PD-1 и TIM-3. Блокада TIGIT и PD-1 in vitro повышает продукцию IFN-γ и TNF-α опухоль-специфическими CD8+ Т клетками. Популяция ранних эффекторных TIL, которые экспрессируют TIGIT и другие ингибиторные рецепторы (LAG-3, TIM-3 и PD-1), но сохраняют их функциональный фенотип, описана у пациентов с раком легкого. Экспрессия TIGIT гена на средблюдается в базальноподобном раке молочной железы, где, подобно другим биомаркерам иммунного распознавания, она ассоциирована с улучшенной выживаемостью в случае этой агрессивной болезни. Ингибиторы TIGIT находятся все еще в ранних фазах исследований, но, по меньшей мере, два агента (MTIG7192A, OMP-313M32) тестируются в клинических изучениях (Таблица 1).

B7-H3

B7-H3 (CD276) является членом B7 суперсемейства иммуномодулирующих лигандов, тесно связанных с B7-H1 (PD-L1), B7-DС (PD-L2), B7-H2 (ICOS-L) и CTLA-4 лигандами B7-1/B7-2 (CD80/CD86).

Роль B7-H3 в иммунной регуляции спорна, поскольку ранние изучения описали его как иммунный костимулятор, но последующие изучения показали коингибиторную роль.

B7-H3 высоко экспрессируется в нормальных тканях, а также в меланоме и различных карциномах; в большинстве случаев экспрессия ассоциирована с более плохими исходами.

Эноблитузумаб (MGA271), моноклональное антитело, таргетирующее B7-H3, ингибирует опухолевый рост в ксенотрансплантатах карцином почки и мочевого пузыря и в настоящее время исследуется по меньшей мере в четырех клинических исследованиях 1 фазы, включая комбинации с пембролизумабом или ипилимумабом. Предварительные результаты единичного агента (NCT01391143) сообщают о хорошей переносимости и уменьшении объема опухолей (2-69% за 12 недель) для несколько типов опухолей. Моноклональное антитело против B7-H3, маркированное иодом 131 для внутриопухолевой доставки и лучевой терапии, показало перспективу в доклинических изучениях и исследуется в клинических исследованиях 1 фазы. MGD009, ретаргетирующий протеин с двойным аффинитетом, биспецифический для B7-H3 и CD3, изучается на сходной стадии (Таблица 1).

Таблица 1. Обзор последних и современных клинических исследований использования ингибиторов иммунных чекпоинтов в канцере.

VISTA

V—domain containing Ig Suppressor of T cell Activation (VISTA, другие названия PD-1H, DD1a; имя гена DIES1), недавно открытый иммуно-регуляторный протеин со структурой, подобной B7 Ig суперсемейству, которое включает PD-L1, экспрессируемый в лимфоидных органах и на миелоидных клетках. Функции VISTA как иммуносупрессорного рецептора и лиганда на Т-клетках, понижаемая IFN-γ и TNFα, блокирует пролиферацию Т клеток и повышает конверсию наивных Т-клеток в регуляторные Т клетки.

В мышиных моделях, блокада VISTA повышает иммунную инфильтрацию опухолей, предпочтительно уменьшая супрессорные клетки миелоидного происхождения. Комбинирование анти-VISTA и анти-PDL1 агентов уменьшает объем опухоли и повышает выживаемость. У людей VISTA+ TIL наблюдаются у 46% пациентов с раком желудка с небольшим процентом опухолевых клеток, также экспрессирующих VISTA. Oliveira P с соавт. показал, что эпигенетические факторы могут регулировать экспрессию VISTA в раковых клетках желудка и что VISTA ассоциирован с фенотипом эпителиально-мезенхимального транзита. У пациентов с плоскоклеточной карциномой полости рта экспрессия VISTA ассоциирована с плохой полной выживаемостью в случае низкого количества CD8+ TIL [102]. VISTA+ TIL и макрофаги повышенно регулируются у пациентов с раком простаты и с меланомой после терапии ипилимумабом (анти-CTLA-4) с большим процентом VISTA+ макрофагов с иммуносупрессорным M2 фенотипом, предполагая, что VISTA может представлять компенсаторный механизм резистентности. Начаты клинические исследования 1 фазы анти-VISTA агентов (Таблица 1) с комбинаторными стратегиями, ожидаемыми после установления безопасности агентов.

Костимуляторные рецепторы лимфоцитов

ICOS и ICOS-L

Inducible T-cell Costimulator (ICOS, CD278, H4, AILIM) is a receptor in the CD28 family of B7-binding proteins [104–106], expressed primarily by activated T cells [107–110]. Upon binding of ligand ICOSL (B7-H2, B7 h, GL50, B7RP-1, LICOS, KIAA0653) expressed mainly on antigen presenting cells [111–118] ICOS enhances Th1 and Th2 function largely through augmented production of effector cytokines (IL-4, IL-5, IL-10, IL-21, IFNγ, TNFα) [104,108,110,119,120].

Expression of ICOS and ICOS-L has been observed in human cancers, with variable prognostic implications [121–128]. Mice and human clinical trial patients treated with anti-CTLA-4 or anti-PD-1 agents exhibit an increased treatment response in the presence of ICOS-hi T cells [129–135], suggesting the latter may be a marker of clinical benefit [131,136]. ICOS knockout mice do not respond well to anti-CTLA-4 therapy [137], whereas concomitant CTLA-4 blockade and ICOS stimulation has a superior anti-tumor effect [129]. Together, these results suggest that the ICOS pathway is critical for effective response to CTLA4 (and perhaps other immune checkpoint) inhibition. Similar to TIM-3, it is unlikely that ICOS-agonists will be pursued as a monotherapy, as they do not independently induce a cytotoxic immune response [138]. Based on encouraging results in preclinical animal models [139], an ICOS agonist antibody JTX-2011 is being investigated in the phase 1 ICONIC clinical trial in combination with nivolumab (NCT02904226), and has so far been well-tolerated [140]; ICOS agonist GSK3359609 is also being evaluated in phase I trials (INDUCE-1, NCT02723955) in combination with pembrolizumab (Table 1).

CD27 и CD70

Members of the tumor necrosis factor (TNF) receptor superfamily contribute to immune upregulation by a mechanism of action different from B7/CD28 co-stimulatory interactions. One well-known member, CD27, is expressed exclusively on lymphocytes [141–144]. Even naпve CD4+ and CD8+ T-cells express low levels CD27; upon activation, CD27 is strongly upregulated on cell surfaces [145] and shed in a soluble form [146,147]. CD27 signalling is limited by the degree of expression of its ligand CD70, which is restricted to T cells, B cells, and dendritic cells following activation of an antigen receptor [148–151]. CD27/CD70 signalling boosts T-cell clonal expansion and survival [152–158], promotes effector and memory T-cell differentiation [152,154,157,159–166], and enhances activation and function of B and NK  cells  [151,167–172].

In a transgenic mouse model, forced expression of CD70 constitutively activates the CD27/CD70 axis, upregulating effector T cells [173] and protecting against tumor development [174]. CD27 agonist therapy also prevents tumor formation or progression in immunocompetent preclinical mouse models [171,175–179]. Varlilumab, a CD27 agonist, is being investigated in multiple early phase clinical trials alone and in combination with anti-PD-1 (Table 1). Preliminary results report that varlilumab treatment upregulates chemokine production, T-cell stimulation, and Treg depletion; 8/31 melanoma/renal cell carcinoma patients had stable disease (SD) at 3 months [180], and of 15 lymphoma patients in a different study, there was 1 partial response (77% reduction) and 3 SD [181]. The related strategy of targeting CD70 is the subject of three antibody-drug conjugates and one monoclonal antibody undergoing clinical trials (Table 1). MDX-1203 (NCT00944905) was well-tolerated and achieved SD in 16/23 (69%) of patients. [182]. SGN-75, an antibody-drug conjugate linking an antiCD70 antibody with cytotoxic agent monomethyl auristatin F (NCT01015911), was also well-tolerated and elicited responses in renal cell carcinomas and lymphomas; however, development was discontinued in favour of a new antibody drug conjugate, SGNeCD70A, in which an anti-CD70 antibody is conjugated to pyrrolobenzodiazepine (NCT02216890).

GITR

Glucocorticoid-Induced TNF Receptor (GITR) — трансмембранный рецептор II типа , член суперсемейства TNFR, конститутивно экспрессируемый на регуляторных Т клетках и индуцируемый на активных CD8+ и CD4+ Т клетках. GITR связывание с GITR-L (экспрессируемый на антиген-представляющих клетках), ингибирует активность Treg и стимулирует эффекторные Т-клетки, делая активацию GITR привлекательной стратегией противоопухолевой иммунотерапии.

Много доклинических сообщений о GITR противоопухолевой in vivo активности использовали мышиное GITR агонистическое моноклональное антитело IgG1 (DTA-1) в мышиных моделях солидного рака. GITR агонизм в дополнение к истощению и ингибированию Treg (подобно CTLA-4 антагонистам и OX40 агонистам), супрессирует продукцию IL-10 и супрессорные клетки миелоидного ростка. Комбинирование GITR агонистов с другими иммуномодулирующими агентами ведет к аддитивным противоопухолевым эффектам.  Одна из наиболее интересных находок этих изучений — то, что GITR агонисты супрессируют рост опухоли и повышают выживаемость не только в моделях иммуногенных опухолей (толстый кишечник, мочевой пузырь, легкое, меланома), но также и в слабо иммуногенных опухолях (молочной железы, мышиной модели меланомы B16, яичника), помещая GITR агонистов в уникальную позицию по сравнению с другими ингибиторами иммунных чекпоинтов, для которых предуществующий иммунитет, видимо, является предпосылкой для их эффективности. Иммуногистохимически или проточной цитометрией, об экспрессии GITR сообщили во многих солидных опухолях человека. У больных с раком молочной железе и эндометрия, GITR экспрессия на Treg выше в TIL, чем в периферической крови. Прогностическое значение GITR+ TIL еще не изучено полностью. По меньшей мере четыре GITR агониста исследуются одни и в комбинациях с другими ингибиторами чекпоинтов в клинических исследованиях ранней фазы (Таблица 1).

Врожденный иммунитет

Макрофагальные чекпоинты

CD47 и SIRPα

CD47, первоначально идентифицированный как Integrin-Associated Protein (IAP), является иммуноглобулином клеточной поверхности, который негативно регулирует противоопухолевый иммунитет посредством супрессии фагоцитоза. Экспрессируемый повсеместно в нормальных тканях, CD47 функционирует, в частности, для защиты жизнеспособные эритроциты от фагоцитоза. Сигналинг вызывается взаимодействием с его лигандом SIRPα (сигнал-регуляторный протеин α), иммуноглобулином клеточной поверхности, преимущественно экспрессируемым макрофагами и дендритными клетками.

Activation of SIRPα by CD47 suppresses phagocytosis by preventing myosin-II accumulation at the phagocytic synapse and suppressing the respiratory burst. T-cell activation is secondarily decreased as an indirect result of reduced tumor cell ingestion by antigen-presenting cells; furthermore, activation of CD47 on naпve T-cells promotes the formation of Tregs and inhibits formation of T helper 1 effector cells.

Overexpression of CD47 has been observed across most cancers [218–225], suggesting that malignant cells exploit the CD47/SIRPα “don’t eat me” signal to evade phagocytosis. In translational studies, high CD47 mRNA expression levels correlate with poor clinical outcomes. [223,225–233] In vitro, CD47/SIRPα blockade induces phagocytosis of cancer cells by human and mouse macrophages [221–223,225,226]. Anti-CD47 monoclonal antibodies have impressive activity in xenograft models [221–226,234,235], although because human CD47 binds exceptionally well to the SIRPα of the NOD-scidIL2Rgammanull mice used [236,237], some studies may overestimate the degree of efficacy [238].

Many early phase clinical trials are in progress targeting the CD47/ SIRPα axis (Table 1). Toxicity data has been presented for NCT02216409, a trial investigating anti-CD47 antibody Hu5F9-G4, [235] which was well-tolerated in 16 patients with advanced solid tumors.

IDO

Indoleamine-2,3-dioxygenase (IDO) is an intracellular enzyme, which in the immune compartment is found in macrophages and dendritic cells, where it catalyzes the first, rate-limiting step of tryptophan catabolism. In converting tryptophan to kynurenine, IDO impacts immune surveillance in two ways: 1) depletion of tryptophan impairs T-cell proliferation due to amino acid insufficiency, and 2) kynurenine induces apoptosis of Th1 cells and promotes differentiation of naive T cells to regulatory T cells. This generates an immune-privileged environment, as seen in the placenta, where IDO was first isolated.

Numerous cancer types have been shown to constitutively express IDO. Transfecting cell lines with IDO prevents their rejection in tumor antigen-immunized mice, an effect reversible with IDO inhibitors. Pharmacological inhibition of IDO has been shown in numerous mouse tumor models to stimulate a robust T cell response and inhibit tumor progression. The tumor suppressor BIN1, which controls expression of IDO, is deficient in numerous cancers; BIN1 knockout induces higher levels of IFNγ-stimulated IDO expression and results  in larger tumors in immunocompetent mouse models compared to controls.

There are presently four small molecule inhibitors of IDO under investigation in clinical trials. One of these, epacadostat, is registered to 20 clinical trials, including one phase 3 trial, and in patients with advanced malignancies, stable disease =16 weeks was observed in 7/52 patients (no objective response). In combination with anti-PD-1 agent pembrolizumab, reductions in tumor burden were observed in 15/19 patients with advanced solid malignancies, including 2 complete responses in melanoma patients.

Чекпоинты естественных киллерных клеток

KIR семейство

KIR (Killer Immunoglobulin-like Receptor) семейство состоит из высоко полиморфных генов, экспрессируемых на клеточной мембране большинства NK и некоторых Т клеток. Некоторые члены KIR семейства (KIR2DL1-3, KIR3DL1) ассоциируются с ингибиторными функциями путем связывания с MHC молекулами (HLA-C/HLA-B). Экспрессия KIR на NK клетках представляет один из механизмов обучения NK клеток от самораспознавания. Сильные взаимодействия между ингибиторными KIR рецепторами и HLA лигандами могут преодолевать NK активирующие сигналы.

Вследствие своей высоко полиморфной природы, различные KIR гены и лиганды влияют на риск заболевания, включая аутоиммунитет и рак. Комбинации KIR генов KIR и специфических лигандов ассоциированы с риском рака. Активирующие KIR гены (KIR2DS2, KIR2DS3 и KIR2DS4) ассоциированы с улучшенной выживаемостью пациентов с колоректальным раком и глиобластомой. Активирующие KIR гены (KIR2DS2, KIR2DS3 и KIR2DS4) ассоциированы с улучшенной выживаемостью в колоректальном раке и пациентах с глиобластомой. В мышиных моделях сконструированные химерные антигенные рецепторы, экспрессирующие NK-активирующий KIR2DS2, показывают более высокую эффективность, чем традиционные костимуляторные молекулы.

Несмотря на обещающие доклинические результаты, единичный клинически исследуемый агент для миеломной болезни фазы 1/2 IPH2101, антительный ингибитор KIR2DL1, 2, и 3 (IPH2101), не показывал ответов болезни. Последующее коррелативное изучение показывало, что мононуклеары периферической крови пациентов, которые лечили in vitro с IPH2101, вели к удалению KIR2DL1 на NK клетках трогоцитозом из FcγRI-экспрессирующих антиген-представляющих клеток. Соответственно, наблюдалось уменьшение цитотоксической активности NK клеток, которое могло объяснить неспособность активировать NK клетки у пациентов в клиническом исследовании. Другой KIR2DL1/2/3 ингибитор (IPH2102, лирилумаб) в настоящее время находится в клинических исследованиях фазы 1/2 в распространенных солидных раках и гемобластозах в комбинации с PD-1 или CTLA-4 блокадой (Таблица 1). Предварительные результаты сообщают, что обнадеживающая объективная величина ответа 24% у пациентов с распространенным раком головы и шеи, леченных лирилумабом в комбинации с анти-PD1 (ниволумабом).

CD94/NKG2A

CD94 — рецептор инвариантной цепи, который на NK клетках может формировать ингибиторный гетеродимер с членом лектин C типа-подобного семейства NKG2A или активирующий гетеродимер с NKG2C или E. Т клетки также могут экспрессировать CD94/NKG2A рецептор (хотя к меньшей степени по сравнению с NK клетками), где он функционирует как преобладающий ингибиторный чекпоинт. Связывание с MHC I класса (HLA-E) опосредует ингибиторную функцию CD94/NKG2A после лигации TCR. CD94/NKG2A-HLA-E взаимодействие может блокироваться таргетингом ERAP-1, протеин, необходимого для обеспечения функциональныи лигандами для CD94/NKG2A на HLA-E молекулах.

CD94/NKG2A как активную мишень для противоопухолевой иммунотерапии. Действительно, множественные изучения сообщают о присутствии CD94/NKG2A+ клеток у онкологических больных. Образцы крови от молодых пациентов с колоректальным раком показывают повышенное число NKG2A+ NK клеток с более низкой цитотоксической активностью по сравнению с образцами от здорового контроля.

Экспрессия NKG2A на NK клетках выше в опухолях против периферической крови пациентов с раком легкого и раком шейки матки.

В небольшой когорте пациентов с раком полости рта сообщили о более высокой частоте NKG2A+ NK, инфильтрирующих опухоль по сравнению с нормальной слизистой оболочкой. Самая высокая экспрессия NKG2A+ NK клеток наблюдались в гнездах рака с низким количеством CD8+ TIL, которые были негативны для Ki67. В гепатоцеллюлярной карциноме большое число NKG2A+ NK клеток найдены во внутриопухолевом по сравнению с перитуморальными регионами. Эти находки поддерживают релевантность NKG2A ингибиторных механизмов как важный путь иммунной эвазии в опухолях человека. Пр по ходят меньшей мере шесть клинических исследований 1/2 фаз изучают IPH2201 антитело, таргетирующее NKG2A у больных с различными карциномами поздних стадий, некоторые в комбинации с PD-L1 ингибиторами (Таблица 1).

Дискуссия

The success of early immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1 has led to a surge in research and development of resources devoted to cancer immunotherapy. How these emerging targets and drugs will be incorporated into the clinical practice is one of the major focuses of clinical cancer research today. There is evidence for additive anti-tumor activity but also higher adverse effects of strategies combining CTLA-4 and PD-1 checkpoint inhibitors [1,2]. Many agents listed in this review are being evaluated in combination with PD1 and/or CTLA-4 inhibitors (Table 1), with unresolved issues including not only efficacy and toxicity, but also optimal sequential delivery in patients and identification of predictive biomarkers of response.

At present, few predictive biomarkers of response to immune checkpoint inhibitors are in use. The best tests to support PD-1/PD-L1 agents are a subject of great controversy, and most new agents do not have validated companion biomarkers. However, inflamed tumors are associated with an elevated response to immune checkpoint inhibitors, and frequently comprise tumors with a high mutational load or with microsatellite instability[13,298], the latter now considered an FDA-approved biomarker for pembrolizumab independent of tumor site or histology. Immune response profiling by next generation  panel sequencing or technologies such as NanoString may also prove useful in this regard and are a subject of active research in clinical trial correlative science studies. In contrast, immune-desert (socalled “cold”) tumors have only modest responses to immune checkpoint inhibitors and may need to  be treated  using  immunostimulatory approaches [299]. Clinical trial designs that include assessment of immune biomarkers (e.g., T cell receptor sequencing), access to early on-treatment biopsies for immune monitoring, and identification of peripheral blood biomarkers that correlate with the tumor immune microenvironment may help to address these issues.

Заключение

This field is rapidly advancing and extremely active for drug development and clinical trials. Toxicities still need to be determined, particularly of combination strategies, which risk enhanced autoimmune side effects. Given limited resources and patients available for clinical trials, emerging agents with acceptable toxicity will need to be prioritized based on factors including not only the strength of evidence implicating their role in cancer immuno-oncology, but also their frequency of expression in areas of clinical need not well-served by existing agents. While many of these agents may not ultimately find a place in the growing armamentarium of anticancer immuno-oncology drugs, the pathways under investigation are so many, and the early data so promising, that it is likely that several truly effective new treatment strategies will emerge.

Литература

[1] M. Reck, D. Rodrнguez-Abreu, A.G. Robinson, R. Hui, T. Csoszi, A. Fьlцp, et al., Pembrolizumab versus chemotherapy for PD-L1-Positive non-Small-Cell lung cancer, N. Engl. J. Med. Massachusetts Med. Soc. 375 (November (19)) (2016) 1823–1833.

[2] J. Larkin, V. Chiarion-Sileni, R. Gonzalez, J.J. Grob, C.L. Cowey, C.D. Lao, et al., Combined nivolumab and ipilimumab or monotherapy in untreated melanoma, N. Engl. J. Med. Massachusetts Med. Soc. 373 (July (1)) (2015) 23–34.

[3] P. Sharma, S. Hu-Lieskovan, J.A. Wargo, A. Ribas, Primary, adaptive, and acquired resistance to cancer immunotherapy, Cell 168 (Febuary (4)) (2017) 707–723.

[4]  A.C. Anderson, N. Joller, V.K. Kuchroo, Lag-3, tim-3, and TIGIT: Co-inhibitory receptors with specialized functions in immune regulation, Immunity 44 (May(5)) (2016)    989–1004.

[5]  M. Scurr, K. Ladell, M. Besneux, A. Christian, T. Hockey, K. Smart, et al., Highly prevalent colorectal cancer-infiltrating LAP? Foxp3? T cells exhibit more potent immunosuppressive activity than Foxp3? regulatory T cells, Mucosal Immunol. 7 (March (2)) (2014) 428–439 (Nature Publishing Group).

[6] M. Bettini, A.L. Szymczak-Workman, K. Forbes, A.H. Castellaw, M. Selby, X. Pan, et al., Cutting edge: accelerated autoimmune diabetes in the absence of LAG-3, J. Immunol. Am. Assoc. Immunol. 187 (October (7)) (2011) 3493–3498.

[7] J.B. Williams, B.L. Horton, Y. Zheng, Y. Duan, J.D. Powell, T.F. Gajewski, The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment, J. Exp. Med. 214 (Febuary (2))  (2017)   381–400.

[8]  C. Casati, C. Camisaschi, F. Rini, F. Arienti, L. Rivoltini, F. Triebel, et al., Soluble human LAG-3 molecule ampli?es the in vitro generation of type 1 tumor-specific immunity, Clinical Cancer Research. American Association for Cancer Research; 66  (April  (8))  (2006)  4450–4460.

[9]  M. Shapiro, Y. Herishanu, B.-Z. Katz, N. Dezorella, C. Sun, S. Kay, et al., Lymphocyte activation gene 3: a novel therapeutic target in chronic lymphocytic leukemia,  Haematologica  102  (May  (5))  (2017)  874–882.

[10] E. Tassi, G. Grazia, C. Vegetti, I. Bersani, G. Bertolini, A. Molla, T. et al. Early Effector, Lymphocytes coexpress multiple inhibitory receptors in primary nonSmall cell lung cancer, Clin. Cancer Res. 77 (Febuary (4)) (2017) 851–861.

[11]  G. Bottai, C. Raschioni, A. Losurdo, L. Di Tommaso, C. Tinterri, R. Torrisi, et al., An immune strati?cation reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers, Breast Cancer Res. BioMed Cen. 18 (December(1)) (2016) 121.

[12]  W.-W. Deng, L. Mao, G.-T. Yu, L.-L. Bu, S.-R. Ma, B. Liu, et al., LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma,  Oncoimmunology  5 (11)  (2016) e1239005.

[13] N.J. Llosa, M. Cruise, A. Tam, E.C. Wicks, E.M. Hechenbleikner, J.M. Taube, et al., The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints, Cancer Discovery Am. Assoc. Cancer  Res.  5  (January  (1))  (2015)  43–51.

[14] Q. Meng, Z. Liu, E. Rangelova, T. Poiret, A. Ambati, L. Rane, et al., Expansion of tumor-reactive t cells from patients with pancreatic cancer, J. Immunother. 39 (Febuary (2)) (2016) 81–89.

[15] C.E. Demeure, J. Wolfers, N. Martin-Garcia, P. Gaulard, F. Triebel, T Lymphocytes infiltrating various tumour types express the MHC class II ligand lymphocyte activation gene-3 (LAG-3): role of LAG-3/MHC class II interactions in cell–cell  contacts, Eur. J. Cancer 37 (September (13)) (2001) 1709–1718.

[16] S.-R. Woo, M.E. Turnis, M.V. Goldberg, J. Bankoti, M. Selby, C.J. Nirschl, et al., Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape, Clin. Cancer Res. Am. Assoc. Cancer Res. 72 (Febuary (4)) (2012) 917–927.

[17] R.-Y. Huang, C. Eppolito, S. Lele, P. Shrikant, J. Matsuzaki, K. Odunsi, LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model, Oncotarget Impact J. 6 (September (289)) (2015) 27359–27377.

[18]  R.-Y. Huang, A. Francois, A.R. McGray, A. Miliotto, K. Odunsi, Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer, Oncoimmunology 6 (1) (2017) e1249561  (Taylor & Francis).

[19]  C. Brignone, B. Escudier, C. Grygar, M. Marcu, F. Triebel, A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma, Clin. Cancer Res. 15 (October (19)) (2009)     6225–6231.

[20] L. Monney, C.A. Sabatos, J.L. Gaglia, A. Ryu, H. Waldner, T. Chernova, et al., Th1specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease, Nature 415 (January (6871)) (2002) 536–541.

[21] W.D. Hastings, D.E. Anderson, N. Kassam, K. Koguchi, E.A. Green?eld, S.C. Kent, et al., TIM-3 is expressed on activated human CD4+ T cells and regulates Th1 and Th17 cytokines, Eur. J. Immunol. 39 (September (9)) (2009) 2492–2501 (WILEYVCH Verlag;).

[22]  X. Gao, Y. Zhu, G. Li, H. Huang, G. Zhang, F. Wang, et al., TIM-3 expression characterizes regulatory T. cells in tumor tissues and is associated with lung cancer progression, PLoS One 7 (2) (2012) e30676 (Public Library of Science M.P. Bachmann).

[23] J. Yan, Y. Zhang, J.-P. Zhang, J. Liang, L. Li, L. Zheng, Tim-3 expression de?nes  regulatory T cells in human tumors, PLoS One 8 (3) (2013) e58006 (J. Zimmer).

[24]  M.K. Gleason, T.R. Lenvik, V. McCullar, M. Felices, M.S. O’Brien, S.A. Cooley,

et al., Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9, Blood Am. Soc. Hematol. 119  (March  (13))  (2012)  3064–3072.

[25]  L.C. Ndhlovu, S. Lopez-Vergиs, J.D. Barbour, R.B. Jones, A.R. Jha, B.R. Long, et al., Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity, Blood Am. Soc. Hematol. 119 (April (16)) (2012) 3734–3743.

[26]  A.C. Anderson, D.E. Anderson, L. Bregoli, W.D. Hastings, N. Kassam, C. Lei, et al., Promotion of tissue in?ammation by the immune receptor tim-3 expressed on  innate  immune  cells,  Science  318  (November  (5853))  (2007)  1141–1143.

[27] J. Wada, Y.S. Kanwar, Identification and characterization of galectin-9, a novel beta-galactoside-binding mammalian lectin, J. Biol. Chem. 272 (Febuary (9)) (1997) 6078–6086.

[28] C. Zhu, A.C. Anderson, A. Schubart, H. Xiong, J. Imitola, S.J. Khoury, et al., The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity, Nat. Immunol. 6 (December (12)) (2005) 1245–1252.

[29] C.A. Sabatos, S. Chakravarti, E. Cha, A. Schubart, A. Sбnchez-Fueyo, X.X. Zheng, et al., Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance, Nat. Immunol. 4 (November (11)) (2003) 1102–1110.

[30] A. Sбnchez-Fueyo, J. Tian, D. Picarella, C. Domenig, X.X. Zheng, C.A. Sabatos, et al., Tim-3 inhibits T helper type 1-mediated autoand alloimmune responses

and promotes immunological tolerance, Nat. Immunol. 4 (November (11)) (2003) 1093–1101.

[31]  R.B. Jones, L.C. Ndhlovu, J.D. Barbour, P.M. Sheth, A.R. Jha, B.R. Long, et al., Tim-3 expression de?nes a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection, J. Exp. Med. 205 (November (12))  (2008)  2763–2779.

[32] D.A. Ha?er, V. Kuchroo, TIMs central regulators of immune responses, J. Exp. Med. 205 (November (12)) (2008) 2699–2701 (Rockefeller University Press).

[33]  L. Golden-Mason, B.E. Palmer, N. Kassam, L. Townshend-Bulson, S. Livingston, B.J. McMahon, et al., Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells, J. Virol. Am. Soc. Microbiol. 83 (September (18)) (2009) 9122–9130.

[34] S. Takamura, S. Tsuji-Kawahara, H. Yagita, H. Akiba, M. Sakamoto, T. Chikaishi, et al., Premature terminal exhaustion of Friend virus-specific effector CD8+ T cells by rapid induction of multiple inhibitory receptors, J. Immunol. Am. Assoc. Immunol. 184 (May (9)) (2010) 4696–4707.

[35]  H.-T. Jin, A.C. Anderson, W.G. Tan, E.E. West, S.-J. Ha, K. Araki, et al., Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection, Proc. Natl. Acad. Sci. U. S. A. 107 (August (33)) (2010) 14733–14738.

[36] J. Fourcade, Z. Sun, M. Benallaoua, P. Guillaume, I.F. Luescher, C. Sander, et al., Upregulation of Tim-3 and PD-1 expression is associated with tumor antigenspecific CD8+ T cell dysfunction in melanoma patients, J. Exp. Med. 10 (2010) 2175–2186 (Rockefeller University Press).

[37]  L. Baitsch, P. Baumgaertner, E. Devкvre, S.K. Raghav, A. Legat, L. Barba, et al., Exhaustion of tumor-specific CD8к T cells in metastases from melanoma patients,

1. Clin. Invest. Am. Soc. Clin. Invest. 121 (June (6)) (2011) 2350–2360.

[38]  Z.-Z. Yang, D.M. Grote, S.C. Ziesmer, T. Niki, M. Hirashima, A.J. Novak, et al., IL12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma, J. Clin. Invest. Am. Soc. Clin. Invest. 122 (April  (4))  (2012)  1271–1282.

[39]  Y. Zong, S. He, Identification of Co-inhibitory receptors PD-1 and TIM-3 on t cells from gastric cancer patients, Immunother.: Open Access OMICS Int. 01 (01) (2016).

[40] X. Lu, L. Yang, D. Yao, X. Wu, J. Li, X. Liu, et al., Tumor antigen-specific CD8(+) T cells are negatively regulated by PD-1 and Tim-3 in human gastric cancer, Cell. Immunol. 313 (March) (2017) 43–51.

[41]  R. Linedale, C. Schmidt, B.T. King, A.G. Ganko, F. Simpson, B.J. Panizza, et al., Elevated frequencies of CD8T cells expressing PD-1, CTLA-4 and Tim-3 within tumour from perineural squamous cell carcinoma patients. Karagiannis SN, editor, PLoS  One  12  (4)  (2017)  e0175755.

[42]  Z. Li, X. Liu, R. Guo, P. Wang, TIM-3 plays a more important role than PD-1 in the functional impairments of cytotoxic T cells of malignant Schwannomas, Tumour Biol. 39 (May (5)) (2017) (SAGE PublicationsSage UK: London, England 1010428317698352).

[43] G. Shayan, R. Srivastava, J. Li, N. Schmitt, L.P. Kane, R.L. Ferris, Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer, Oncoimmunology 6 (1) (2017) e1261779.

[44] G.L. Ceresoli, A. Mantovani, Immune checkpoint inhibitors in malignant pleural mesothelioma, Lancet Oncol. 18 (May (5)) (2017) 559–561 Elsevier.

[45] K. Sakuishi, L. Apetoh, J.M. Sullivan, B.R. Blazar, V.K. Kuchroo, A.C. Anderson, Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore antitumor immunity, J. Exp. Med. 208 (6) (2011) (Rockefeller University

Press1331-1).

[46]  Q. Zhou, M.E. Munger, R.G. Veenstra, B.J. Weigel, M. Hirashima, D.H. Munn,

et al., Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia, Blood Am. Soc. Hematol.  117  (April  (17))  (2011)  4501–4510.

[47] A.-S. Gautron, M. Dominguez-Villar, M. de Marcken, D.A. Ha?er, Enhanced suppressor function of TIM-3+ FoxP3+ regulatory T cells, Eur. J. Immunol. 44 (September (9)) (2014) 2703–2711.

[48] S. Gupta, T.B. Thornley, W. Gao, R. Larocca, L.A. Turka, V.K. Kuchroo, et al., Allograft rejection is restrained by short-lived TIM-3+ PD-1+ Foxp3+ tregs, J. Clin. Invest. Am. Soc. Clin. Invest. 122 (July (7)) (2012) 2395–2404.

[49]  I.P. da Silva, A. Gallois, S. Jimenez-Baranda, S. Khan, A.C. Anderson, V.K. Kuchroo, et al., Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade, Cancer Immunol. Res. 2 (May(5)) (2014) 410–422.

[50] C.-W. Kang, A. Dutta, L.-Y. Chang, J. Mahalingam, Y.-C. Lin, J.-M. Chiang, et al., Apoptosis of tumor infiltrating effector TIM-3+ CD8+ T cells in colon cancer, Sci. Rep. 5 (October (1)) (2015) 15659 Nature Publishing Group.

[51]  S.F. Ngiow, B. Scheidt von, H. Akiba, H. Yagita, Teng Mwl, M.J. Smyth, Anti-TIM3 antibody promotes T. cell IFN-γ–Mediated antitumor immunity and suppresses established tumors, Clin. Cancer Res. Am. Assoc. Cancer Res. 71 (May (10)) (2011) 3540–3551.

[52]  S. Koyama, E.A. Akbay, Y.Y. Li, G.S. Herter-Sprie, K.A. Buczkowski, W.G. Richards, et al., Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints, Nat. Commun. 17 (Febuary (7)) (2016) 10501 (Nature Publishing Group).

[53]  W.C. Dougall, S. Kurtulus, M.J. Smyth, A.C. Anderson, TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy, Immunol. Rev. 276 (March  (1))  (2017)  112–120.

[54] F.A. Deuss, B.S. Gully, J. Rossjohn, R. Berry, Recognition of nectin-2 by the natural killer cell receptor TIGIT, J. Biol. Chem. (May) (2017) 786483 (jbc.M117).

[55]  S.D. Levin, D.W. Taft, C.S. Brandt, C. Bucher, E.D. Howard, E.M. Chadwick, et al., Vstm3 is a member of the CD28 family and an important modulator of T-cell function, Eur. J. Immunol. 41 (April (4)) (2011) 902–915 (WILEY-VCH Verlag).

[56] R.J. Johnston, L. Comps-Agrar, J. Hackney, X. Yu, M. Huseni, Y. Yang, et al., The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function, Cancer Cell 26 (December (6)) (2014) 923–937 (Elsevier).

[57] S. Kurtulus, K. Sakuishi, S.F. Ngiow, N. Joller, D.J. Tan, Teng Mwl, et al., TIGIT predominantly regulates the immune response via regulatory T cells, J Clin. Invest. Am. Soc. Clin. Invest. 125 (November (11)) (2015) 4053–4062.

[58] F. Wang, H. Hou, S. Wu, Q. Tang, W. Liu, M. Huang, et al., TIGIT expression levels on human NK cells correlate with functional heterogeneity among healthy individuals, Eur. J. Immunol. 45 (October (10)) (2015) 2886–2897.

[59] J.-M. Chauvin, O. Pagliano, J. Fourcade, Z. Sun, H. Wang, C. Sander, et al., TIGIT and PD-1 impair tumor antigen-specific CD8? T cells in melanoma patients, J. Clin. Invest. Am. Soc. Clin. Invest. 125 (May (5)) (2015) 2046–2058.

[60] D. Sarhan, F. Cichocki, B. Zhang, A. Yingst, S.R. Spellman, S. Cooley, N.K. et al. Adaptive, Cells with low TIGIT expression are inherently resistant to myeloidDerived suppressor cells, Clin. Cancer Res. 76 (October (19)) (2016) 5696–5706.

[61] J. Xie, J. Wang, S. Cheng, L. Zheng, F. Ji, L. Yang, et al., Expression of immune checkpoints in T cells of esophageal cancer patients, Oncotarget. Impact Journals 7 (September (39)) (2016) 63669–63678.

[62]  S. Martнnez-Canales, F. Cifuentes, M. Lуpez De Rodas Gregorio, L. Serrano-Oviedo, E.M. Galбn-Moya, E. Amir, et al., Transcriptomic immunologic signature associated with favorable clinical outcome in basal-like breast tumors, PLoS One 12 (5) (2017)  e0175128  (A.  Perez-Martinez).

[63] A.I. Chapoval, J. Ni, J.S. Lau, R.A. Wilcox, D.B. Flies, D. Liu, et al., B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production, Nat. Immunol. 2 (March (3)) (2001) 269–274.

[64] E. Picarda, K.C. Ohaegbulam, X. Zang, Molecular pathways targeting B7-H3 (CD276) for human cancer immunotherapy, Clin. Cancer Res. 22 (July (14)) (2016)     3425–3431.

[65] X. Sun, M. Vale, E. Leung, J.R. Kanwar, R. Gupta, G.W. Krissansen, Mouse B7-H3 induces antitumor immunity, Gene Ther. 10 (September (20)) (2003) 1728–1734 (Nature Publishing Group).

[66] L. Luo, A.I. Chapoval, D.B. Flies, G. Zhu, F. Hirano, S. Wang, et al., B7-H3 enhances tumor immunity in vivo by costimulating rapid clonal expansion of antigen-specific CD8+ cytolytic T cells, J. Immunol. 173 (November (9)) (2004) 5445–5450.

[67] L. Luo, H. Qiao, F. Meng, X. Dong, B. Zhou, H. Jiang, et al., Arsenic trioxide synergizes with B7H3-mediated immunotherapy to eradicate hepatocellular carcinomas, Int. J. Cancer 118 (April (7)) (2006) 1823–1830 (Wiley Subscription Services, Inc., A Wiley Company).

[68] L. Wang, C.C. Fraser, K. Kikly, A.D. Wells, R. Han, A.J. Coyle, et al., B7-H3 promotes acute and chronic allograft rejection, Eur. J. Immunol. 35 (Febuary (2)) (2005) 428–438 (WILEY-VCH Verlag).

[69] C.M. Lupu, C. Eisenbach, M.A. Kuefner, J. Schmidt, A.D. Lupu, W. Stremmel, et al., An orthotopic colon cancer model for studying the B7-H3 antitumor effect in vivo, J. Gastrointest. Surg. 10 (May(5)) (2006) 635–645.

[70] X. Chen, E.M. Quinn, H. Ni, J. Wang, S. Blankson, H.P. Redmond, et al., B7-H3 participates in the development of experimental pneumococcal meningitis by augmentation of the in?ammatory response via a TLR2-dependent mechanism, J. Immunol. Am. Assoc. Immunol. 189 (July (1)) (2012) 347–355.

[71] L. Luo, G. Zhu, H. Xu, S. Yao, G. Zhou, Y. Zhu, et al., B7-H3 promotes pathogenesis of autoimmune disease and in?ammation by regulating the activity of di?erent t cell subsets, PLoS One 10 (6) (2015) e0130126 (O Frey).

[72] O. Nagashima, N. Harada, Y. Usui, T. Yamazaki, H. Yagita, K. Okumura, et al., B7H3 contributes to the development of pathogenic Th2 cells in a murine model of asthma, J. Immunol. 181 (6) (2008) 4062–4071.

[73]  W.-K. Suh, B.U. Gajewska, H. Okada, M.A. Gronski, E.M. Bertram, W. Dawicki, et al., The B7 family member B7-H3 preferentially down-regulates T helper type 1mediated immune responses, Nat. Immunol. 4 (September (9)) (2003) 899–906.

[74] Prasad Dvr, T. Nguyen, Z. Li, Y. Yang, J. Duong, Y. Wang, et al., Murine B7-H3 is a negative regulator of t cells, J. Immunol. Am. Assoc. Immunolo. 173 (4) (2004) (2500-6).

[75] J. Leitner, C. Klauser, W.F. Pickl, J. Stцckl, O. Majdic, A.F. Bardet, et al., B7-H3 is a potent inhibitor of human T-cell activation: no evidence for B7-H3 and TREML2 interaction, Eur. J. Immunol. 39 (July (7)) (2009) 1754–1764 (WILEY-VCH Verlag).

[76]  R.G. Veenstra, R. Flynn, K. Kreymborg, C. McDonald-Hyman, A. Saha, P.A. Taylor, et al., B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality, Blood Am. Soc. Hematol. 125 (May (21)) (2015)     3335–3346.

[77] T. Ueno, M.Y. Yeung, M. McGrath, S. Yang, N. Zaman, B. Snawder, et al., Intact B7H3 signaling promotes allograft prolongation through preferential suppression of Th1 effector responses, Eur. J. Immunol. 42 (September (9)) (2012) 2343–2353.

[78] V. Ling, P.W. Wu, V. Spaulding, J. Kieleczawa, D. Luxenberg, B.M. Carreno, et al., Duplication of primate and rodent B7-H3 immunoglobulin Vand C-like domains: divergent history of functional redundancy and exon loss, Genomics 82 (September (3)) (2003) 365–377.

[79]  K. Mahnke, S. Ring, T.S. Johnson, S. Schallenberg, K. Schцnfeld, V. Storn, et al., Induction of immunosuppressive functions of dendritic cells in vivo by CD4+ CD25+ regulatory T cells: role of B7-H3 expression and antigen presentation, Eur. J. Immunol. 37 (August (8)) (2007) 2117–2126 (WILEY-VCH Verlag).

[80]  A. Fukushima, T. Sumi, K. Fukuda, N. Kumagai, T. Nishida, T. Yamazaki, et al., B7H3 regulates the development of experimental allergic conjunctivitis in mice, Immunol.  Lett.  113  (October  (1))  (2007)  52–57.

[81]  V. Vigdorovich, U.A. Ramagopal, E. Lбzбr-Molnбr, E. Sylvestre, J.S. Lee, K.A. Hofmeyer, et al., Structure and T cell inhibition properties of B7 family member, B7-H3, Structure 21 (May (5)) (2013) 707–717 Elsevier.

[82] J. Wang, K.K. Chong, Y. Nakamura, L. Nguyen, S.K. Huang, C. Kuo, et al., B7-H3 associated with tumor progression and epigenetic regulatory activity in cutaneous melanoma, J. Invest. Dermatol. 133 (August (8)) (2013) 2050–2080 (Elsevier).

[83] Y. Hu, X. Lv, Y. Wu, J. Xu, L. Wang, W. Chen, et al., Expression of costimulatory molecule B7-H3 and its prognostic implications in human acute leukemia, Hematology 20 (May(4)) (2015) 187–195.

[84] J. Sun, Y.-D. Guo, X.-N. Li, Y.-Q. Zhang, L. Gu, Wu P-P, et al: b7-H3 expression in breast cancer and upregulation of VEGF through gene silence, Onco Targets Ther. 7 (2014) 1979–1986 (Dove Press).

[85]  X. Zang, R.H. Thompson, H.A. Al-Ahmadie, A.M. Serio, V.E. Reuter, J.A. Eastham, et al., B7-H3 and B7 x are highly expressed in human prostate cancer and associated with disease spread and poor outcome, Proc. Natl. Acad. Sci. U. S. A. 104 (49)  (2007)  19458–19463  (Dec  4).

[86]  X. Zang, P.S. Sullivan, R.A. Soslow, R. Waitz, V.E. Reuter, A. Wilton, et al., Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas, Mod. Pathol. 23 (August (8)) (2010) 1104–1112 (Nature Publishing Group).

[87] Y. Chen, J. Sun, H. Zhao, D. Zhu, Q. Zhi, S. Song, et al., The coexpression and clinical signi?cance of costimulatory molecules B7-H1, B7-H3, and B7-H4 in human pancreatic cancer, Onco Targets Ther. 7 (2014) 1465–1472 (Dove Press).

[88] V.A. Ingebrigtsen, K. Boye, J.M. Nesland, A. Nesbakkn, K. Flatmark, Ш. Fodstad, expression in colorectal cancer: associations with clinicopathological parameters and patient outcome, BMC Cancer 14 (1) (2014) 602 (2015 15:1. Aug 20).

[89]  D. Loo, R.F. Alderson, F.Z. Chen, L. Huang, W. Zhang, S. Gorlatov, et al., Development of an fc-Enhanced anti-B7-H3 monoclonal antibody with potent antitumor  activity,  Clin.  Cancer  Res. 18 (14)  (2012) 3834–3845  (Jul 15).

[90] J. Powderly, G. Cote, K. Flaherty, R.Z. Szmulewitz, A. Ribas, J. Weber, et al., Interim results of an ongoing Phase I, dose escalation study of MGA271 (Fc-optimized humanized anti-B7-H3 monoclonal antibody) in patients with refractory B7-H3-expressing neoplasms or neoplasms whose vasculature expresses B7-H3, J Immunother Cancer. BioMed Central 3 (Suppl 2) (2015) H3–B7.

[91]  K. Kramer, B.H. Kushner, S. Modak, N. Pandit-Taskar, P. Smith-Jones, P. Zanzonico, et al., Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma, J. Neurooncol. 97 (3) (2010) 409–418 (Springer US).

[92] M. Ahmed, M. Cheng, Q. Zhao, Y. Goldgur, S.M. Cheal, H.-F. Guo, et al., Humanized a?nity-matured monoclonal antibody 8H9 has potent antitumor activity and binds to FG loop of tumor antigen B7-H3, J. Biol. Chem. Am. Soc. Biochem. Mol. Biol. 290 (50) (2015) 30018–30029 (Dec 11).

[93] D. Loo, J.A. Scribner, T. Son, J. Hooley, T. Hotaling, M. Chiechi, et al., Abstract 1201: Anti-B7-H3 antibody-drug conjugates as potential therapeutics for solid cancer, Clin. Cancer Res. Am. Assoc. Cancer Res. 76 (14 Supplement) (2016) (Jul 15 1201-1).

[94] D.B. Flies, S. Wang, H. Xu, L. Chen, Cutting edge: a monoclonal antibody specific for the programmed death-1 homolog prevents graft-versus-host disease in mouse models, J. Immunol. Am. Assoc. Immunol. 187 (4) (2011) 1537–1541 (Aug 15).

[95] L. Wang, R. Rubinstein, J.L. Lines, A. Wasiuk, C. Ahonen, Y. Guo, et al., VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses, J. Exp. Med. 208 (3) (2011) 577–592 (Mar 14).

[96] I. Le Mercier, W. Chen, J.L. Lines, M. Day, J. Li, P. Sergent, et al., VISTA regulates the development of protective antitumor immunity, Clin. Cancer Res. 74 (7) (2014) 1933–1944 (Apr 1).

[97] L. Wang, I. Le Mercier, J. Putra, W. Chen, J. Liu, A.D. Schenk, et al., Disruption of the immune-checkpoint Vista gene imparts a proin?ammatory phenotype with predisposition to the development of autoimmunity, Proc. Natl. Acad. Sci. U. S. A. 111 (41) (2014) 14846–14851 (Oct 14).

[98]  J.L. Lines, L.F. Sempere, T. Broughton, L. Wang, R. Noelle, VISTA is a novel broadspectrum negative checkpoint regulator for cancer immunotherapy, Cancer Immunol  Res.  2  (June  (6))  (2014)  510–517.

[99] J. Liu, Y. Yuan, W. Chen, J. Putra, A.A. Suriawinata, A.D. Schenk, et al., Immunecheckpoint proteins Vista and PD-1 nonredundantly regulate murine T-cell responses, Proc. Natl. Acad. Sci. U. S. A. 112 (21) (2015) 6682–6687 (May 26).

[100]  C. Bцger, H.-M. Behrens, S. Krьger, C. Rцcken, The novel negative checkpoint regulator VISTA is expressed in gastric carcinoma and associated with PD-L1/PD1: A future perspective for a combined gastric cancer therapy? Oncoimmunology 6 (4)   (2017)   e1293215.

[101] P. Oliveira, J. Carvalho, S. Rocha, M. Azevedo, I. Reis, V. Camilo, et al., Dies1/ VISTA expression loss is a recurrent event in gastric cancer due to epigenetic regulation, Sci. Rep. 6 (October (1)) (2016) 34860 Nature Publishing Group.

[102]  L. Wu, W.-W. Deng, C.-F. Huang, L.-L. Bu, Mao L Yu G-T, et al., Expression of VISTA correlated with immunosuppression and synergized with CD8 to predict survival in human oral squamous cell carcinoma, Cancer Immunol. Immunother. 66  (May(5))  (2017)  627–636  (Springer  Berlin  Heidelberg).

[103] J. Gao, J.F. Ward, C.A. Pettaway, L.Z. Shi, S.K. Subudhi, L.M. Vence, et al., VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer, Nat. Med. 23 (5) (2017) 551–555 (Mar 27).

[104]  A. Hutlo?, A.M. Dittrich, K.C. Beier, B. Eljaschewitsch, R. Kraft, I. Anagnostopoulos, et al., ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28, Nature 16 (December 402) (1999) 21–24 (Nature Publishing Group).

[105] D. Buon?glio, M. Bragardo, V. Redoglia, R. Vaschetto, F. Bottarel, S. Bonissoni, et al., The T cell activation molecule H4 and the CD28-like molecule ICOS are identical, Eur. J. Immunol. 30 (December (12)) (2000) 3463–3467 (WILEY-VCH Verlag GmbH).

[106]  K. Tezuka, T. Tsuji, D. Hirano, T. Tamatani, K. Sakamaki, Y. Kobayashi, Identification and characterization of rat AILIM/ICOS, a novel T-cell costimulatory molecule, related to the CD28/CTLA4 family, Biochem. Biophys. Res. Commun. 276  (1)  (2000)  335–345  (Sep  16).

[107] K.C. Beier, A. Hutlo?, A.M. Dittrich, C. Heuck, A. Rauch, K. Bьchner, et al., Induction, binding specificity and function of human ICOS, Eur. J. Immunol. 30 (December (12)) (2000) 3707–3717.

[108]  A.J. Coyle, S. Lehar, C. Lloyd, J. Tian, T. Delaney, S. Manning, et al., The CD28related molecule ICOS is required for effective T cell-dependent immune responses, Immunity 13 (1) (2000 Jul) 95–105.

[109] H.W. Mages, A. Hutlo?, C. Heuck, K. Bьchner, H. Himmelbauer, F. Oliveri, et al., Molecular cloning and characterization of murine ICOS and identification of B7h as ICOS ligand, Eur. J. Immunol. 30 (April (4)) (2000) 1040–1047.

[110]  A.J. McAdam, T.T. Chang, A.E. Lumelsky, E.A. Green?eld, V.A. Boussiotis, J.S. Duke-Cohan, et al., Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates di?erentiation of CD4+ T  cells, J. Immunol. 165 (9) (2000) 5035–5040 (Nov 1).

[111] M.M. Swallow, J.J. Wallin, W.C. Sha, B7h, a novel costimulatory homolog of B7. 1 and B7. 2, is induced by TNFαlpha, Immunity 11 (October (4)) (1999) 423–432 (Elsevier).

[112] V. Ling, P.W. Wu, H.F. Finnerty, K.M. Bean, V. Spaulding, L.A. Fouser, et al., Cutting edge: identification of GL50, a novel B7-like protein that functionally binds to ICOS receptor, J. Immunol. 164 (4) (2000) 1653–1657 (Feb 15).

[113] S.K. Yoshinaga, J.S. Whoriskey, S.D. Khare, U. Sarmiento, J. Guo, T. Horan, et al., T-cell co-stimulation through B7RP-1 and ICOS, Nature 402 (6763) (1999) 827–832 (Dec 16).

[114] D. Brodie, A.V. Collins, A. Iaboni, J.A. Fennelly, L.M. Sparks, X.N. Xu, et al., LICOS, a primordial costimulatory ligand? Curr. Biol. 10 (6) (2000 Mar 23) 333–336.

[115] S. Wang, G. Zhu, A.I. Chapoval, H. Dong, K. Tamada, J. Ni, et al., Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS, Blood 96 (8) (2000) 2808–2813  (Oct  15).

[116] A. Aicher, M. Hayden-Ledbetter, W.A. Brady, A. Pezzutto, G. Richter, D. Magaletti, et al., Characterization of human inducible costimulator ligand expression and function, J. Immunol. 164 (9) (2000) 4689–4696 (May 1).

[117] S.K. Yoshinaga, M. Zhang, J. Pistillo, T. Horan, S.D. Khare, K. Miner, et al., Characterization of a new human B7-related protein: b7RP-1 is the ligand to the co-stimulatory protein ICOS, Int. Immunol. 12 (October (10)) (2000) 1439–1447.

[118] G. Richter, M. Hayden-Ledbetter, M. Irgang, J.A. Ledbetter, J. Westermann, I. Kцrner, et al., Tumor necrosis factor-alpha regulates the expression of inducible costimulator receptor ligand on CD34(+) progenitor cells during di?erentiation into antigen presenting cells, J. Biol. Chem. Am. Soc. Biochem. Mol. Biol. 276 (49) (2001)  45686–45693  (Dec  7).

[119]  M. Gigoux, J. Shang, Y. Pak, M. Xu, J. Choe, T.W. Mak, et al., Inducible costimulator promotes helper T-cell di?erentiation through phosphoinositide 3-kinase, Proc. Natl. Acad. Sci. U. S. A. 106 (48) (2009) 20371–20376 (Dec 1).

[120] M. Gigoux, A. Lovato, J. Leconte, J. Leung, N. Sonenberg, W.-K. Suh, Inducible costimulator facilitates T-dependent B cell activation by augmenting IL-4 translation, Mol. Immunol. 59 (May(1)) (2014) 46–54.

[121] H. Lee, J.H. Kim, S.Y. Yang, J. Kong, M. Oh, D.H. Jeong, et al., Peripheral blood gene expression of B7 and CD28 family members associated with tumor progression and microscopic lymphovascular invasion in colon cancer patients, J. Cancer Res. Clin. Oncol. 136 (9) (2010) 1445–1452.

[122]  D. Bogunovic, D.W. O’Neill, I. Belitskaya-Levy, V. Vacic, Y.-L. Yu, S. Adams, et al., Immune pro?le and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival, Proc. Natl. Acad. Sci. U. S. A. 106 (48) (2009)  20429–20434  (Dec  1).

[123]  H. Tamura, K. Dan, K. Tamada, K. Nakamura, Y. Shioi, H. Hyodo, et al., Expression of functional B7-H2 and B7.2 costimulatory molecules and their prognostic implications in de novo acute myeloid leukemia, Clin. Cancer Res. 11 (16) (2005) 5708–5717  (Aug  15).

[124] N. Martin-Orozco, Y. Li, Y. Wang, S. Liu, P. Hwu, Y.-J. Liu, et al., Melanoma cells express ICOS ligand to promote the activation and expansion of T-regulatory cells, Clin. Cancer Res. Am. Assoc. Cancer Res. 70 (23) (2010) 9581–9590 (Dec 1).

[125] G.C. Sim, N. Martin-Orozco, L. Jin, Y. Yang, S. Wu, E. Washington, et al., IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients, J. Clin. Invest Am. Soc. Clin. Invest. 124 (January(1)) (2014) 99–110.

[126]  H. Nagase, T. Takeoka, S. Urakawa, A. Morimoto-Okazawa, A. Kawashima, K. Iwahori, et al., ICOS+Foxp3+TILs in gastric cancer are prognostic markers and effector regulatory T cells associated with Helicobacter pylori, Int. J. Cancer 140 (3) (2016) 686–695 (Oct 27).

[127]  Y. Zhang, Y. Luo, S.-L. Qin, Y.-F. Mu, Y. Qi, M.-H. Yu, et al., The clinical impact of ICOS signal in colorectal cancer patients, Oncoimmunology 5 (5) (2016) e1141857  (Taylor & Francis;Mar  10).

[128]  Thibult M-L Le K-S, S. Just-Landi, S. Pastor, F. Gondois-Rey, S. Granjeaud, et al., Follicular B lymphomas generate regulatory t cells via the ICOS/ICOSL pathway and are susceptible to treatment by anti-ICOS/ICOSL therapy, Clin. Cancer Res. Am. Assoc. Cancer Res. 76 (16) (2016) 4648–4660 (Aug 15).

[129]  X. Fan, S.A. Quezada, M.A. Sepulveda, P. Sharma, J.P. Allison, Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy, J. Exp. Med. 211 (4) (2014) 715–725 (Rockefeller University Press;Apr 7).

[130]  C.I. Liakou, A. Kamat, D.N. Tang, H. Chen, J. Sun, P. Troncoso, et al., CTLA-4 blockade increases IFNgamma-producing CD4+ ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients, Proc. Natl. Acad. Sci. U. S. A. 105 (39)  (2008)  14987–14992  (Sep  30).

[131]  B.C. Carthon, J.D. Wolchok, J. Yuan, A. Kamat, Ng. Tang, D.S.J. Sun, et al., Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial, Clin. Cancer Res. Am. Assoc. Cancer Res. 16 (10) (2010)  2861–2871  (May 15).

[132] R.H. Vonderheide, P.M. LoRusso, M. Khalil, E.M. Gartner, D. Khaira, D. Soulieres, et al., Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells, Clin. Cancer Res. 16 (13) (2010) 3485–3494 (Jul 1).

[133] A.O. Kamphorst, R.N. Pillai, S. Yang, T.H. Nasti, R.S. Akondy, A. Wieland, et al., Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients, Proc. Natl. Acad. Sci. U. S. A. 114 (19) (2017) 4993–4998 (National Acad Sciences; May 9).

[134] C. Tang, J.W. Welsh, P. de Groot, E. Massarelli, J.Y. Chang, K.R. Hess, et al., Ipilimumab with stereotactic ablative radiation therapy: phase I results and immunologic correlates from peripheral t cells, Clin. Cancer Res. Am. Assoc. Cancer Res. 23 (6) (2017) 1388–1396 (Mar 15).

[135] A.M. Heeren, B.D. Koster, S. Samuels, D.M. Ferns, D. Chondronasiou, G.G. Kenter, et al., High and interrelated rates of PD-L1+ CD14+ antigen-presenting cells and regulatory t cells mark the microenvironment of metastatic lymph nodes from patients with cervical cancer, Cancer Immunol. Res. Am. Assoc. Cancer Res. 3 (October (1)) (2014) 2014–2058 (canimm.0149).

[136]  A.M. Di Giacomo, L. Calabrт, R. Danielli, E. Fonsatti, E. Bertocci, I. Pesce, et al., Long-term survival and immunological parameters in metastatic melanoma patients who responded to ipilimumab 10тmg/kg within an expanded access programme, Cancer Immunol. Immunother.  62 (June (6))  (2013) 1021–1028 (Springer-Verlag).

[137]  T. Fu, Q. He, P. Sharma, The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy, Clin. Cancer Res. Am. Assoc. Cancer  Res.  71  (August  (16))  (2011)  5445–5454.

[138]  M.H. Nelson, S. Kundimi, J.S. Bowers, C.E. Rogers, L.W. Hu?, K.M. Schwartz, et al., The inducible costimulator augments tc17 cell responses to self and tumor tissue, J. Immunol. Am. Assoc. Immunol. 194 (Febuary (4)) (2015) 1737–1747.

[139] J.S. Michaelson, C.J. Harvey, K.G. Elpek, E. Duong, M. Wallace, C.J. Shu, et al., Abstract 573: Preclinical evaluation of JTX-2011, an anti-ICOS agonist antibody, Clin. Cancer Res. 76 (Suppl. 14) (2016) Jul 22 573–573.

[140]  H.A. Burris, M.K. Callahan, A.W. Tolcher, S. Kummar, G.S. Falchook, R.K. Pachynski, et al., Phase 1 safety of ICOS agonist antibody JTX-2011 alone and with nivolumab (nivo) in advanced solid tumors; predicted vs observed pharmacokinetics (PK) in ICONIC, JCO Am. Soc. Clin. Oncol. (May) (2017) 30.

[141] R.A. Van Lier, J. Borst, T.M. Vroom, H. Klein, P. Van Mourik, W.P. Zeijlemaker, et al., Tissue distribution and biochemical and functional properties of Tp55 (CD27), a novel T cell di?erentiation antigen, J. Immunol. Am. Assoc. Immunol. 139 (September (5)) (1987) 1589–1596.

[142] R.D. Bigler, Y. Bushkin, N. Chiorazzi, S152 (CD27). A modulating disul?de-linked T cell activation antigen, Immunol. Am. Assoc. Immunol. 141 (July (1)) (1988) 21–28.

[143] D. Camerini, G. Walz, W.A. Loenen, J. Borst, B. Seed, The T. cell activation antigen CD27 is a member of the nerve growth factor/tumor necrosis factor receptor gene family, J. Immunol. Am. Assoc. Immunol. 147 (November (9)) (1991) 3165–3169.

[144] L.A. Gravestein, B. Blom, L.A. Nolten, E. de Vries, Horst Gvd, F. Ossendorp, et al., Cloning and expression of murine CD27: comparison with 4-1BB, another lymphocyte-specific member of the nerve growth factor receptor family, Eur. J. Immunol. 23 (April (4)) (1993) 943–950 (WILEY-VCH Verlag GmbH;).

[145] J. Borst, C. Sluyser, E.D. Vries, H. Klein, Melief Cjm, R.A.W. Van Lier, Alternative molecular form of human T cell-specific antigen CD27 expressed upon T cell activation, Eur. J. Immunol. 19 (Febuary (2)) (1989) 357–364 (WILEY-VCH Verlag  GmbH).

[146] Loenen Wam, E. de Vries, L.A. Gravestein, R.Q. Hintzen, Raw. Van Lier, J. Borst, The CD27 membrane receptor, a lymphocyte-specific member of the nerve growth factor receptor family, gives rise to a soluble form by protein processing that does not involve receptor endocytosis, Eur. J. Immunol. 22 (2) (1992) 447–455 (WILEY-VCH Verlag GmbH).

[147] R.Q. Hintzen, R. De Jong, C.E. Hack, M. Chamuleau, E.F. de Vries, Berge ten IJ, et al. A soluble form of the human T cell di?erentiation antigen CD27 is released after triggering of the TCR/CD3 complex, J. Immunol. Am. Assoc. Immunol. 147 (Jul  (1))  (1991)  29–35.

[148] K. Tesselaar, Y. Xiao, R. Arens, Gmw van Schijndel, D.H. Schuurhuis, R.E. Mebius, et al., Expression of the murine CD27 ligand CD70 in vitro and in vivo, J. Immunol. Am. Assoc. Immunolo. 170 (Jan (1)) (2003) 33–40.

[149] Bullock Tnj, H. Yagita, Induction of CD70 on dendritic cells through CD40 or TLR stimulation contributes to the development of CD8+ t cell responses in the absence of CD4+ t cells, J. Immunol. Am. Assoc. Immunol. 174 (Jan (2)) (2005) 710–717.

[150]  P.J. Sanchez, J.A. McWilliams, C. Haluszczak, H. Yagita, R.M. Kedl, Combined TLR/CD40 stimulation mediates potent cellular immunity by regulating dendritic cell expression of CD70 In vivo, J. Immunol. Am. Assoc. Immunol. 178 (Febuary (3))   (2007)   1564–1572.

[151] J. Borst, J. Hendriks, Y. Xiao, CD27 and CD70 in T cell and B cell activation, Curr. Opin. Immunol. 17 (June (3)) (2005) 275–281.

[152] J. Hendriks, Y. Xiao, J. Borst, CD27 promotes survival of activated T cells and complements CD28 in generation and establishment of the effector T cell pool, J. Exp. Med. 198 (November (9)) (2003) 1369–1380 (Rockefeller University Press;).

[153] V. Peperzak, Veraar Eam, A.M. Keller, Y. Xiao, J. Borst, The Pim kinase pathway contributes to survival signaling in primed CD8+ T cells upon CD27 costimulation, J. Immunol. Am. Assoc. Immunol. 185 (December (11)) (2010) 6670–6678.

[154] M.F. van Oosterwijk, H. Juwana, R. Arens, K. Tesselaar, E. van Oers Mhj Eldering, et al., CD27-CD70 interactions sensitise naive CD4+ T cells for IL-12-induced Th1 cell  development,  Int.  Immunol.  19  (June(6))  (2007)  713–718.

[155] D.V. Dol?, A.C. Boesteanu, C. Petrovas, D. Xia, E.A. Butz, P.D. Katsikis, Late signals from CD27 prevent Fas-dependent apoptosis of primary CD8+ T cells, J. Immunol. 180 (Mar (5)) (2008) 2912–2921 (NIH Public Access).

[156] R. Amaravadi, C.B. Thompson, The survival kinases Akt and Pim as potential pharmacological targets, J. Clin. Invest. Am. Soc. Clin. Invest. 115 (October (10)) (2005)   2618–2624.

[157] V. Peperzak, Y. Xiao, Veraar Eam, J. Borst, CD27 sustains survival of CTLs in virusinfected nonlymphoid tissue in mice by inducing autocrine IL-2 production, J. Clin. Invest. Am. Soc. Clin. Invest. 120 (January (1)) (2010) 168–178.

[158] J.M. Carr, M.J. Carrasco, Thaventhiran Jed, P.J. Bambrough, M. Kraman, A.D. Edwards, et al., CD27 mediates interleukin-2-independent clonal expansion of the CD8+ T cell without effector di?erentiation, Proc. Natl. Acad. Sci. 103 (December   (51))   (2006)   19454–19459.

[159] J. Hendriks, L.A. Gravestein, K. Tesselaar, R.A. Van Lier, T.N. Schumacher, J. Borst, CD27 is required for generation and long-term maintenance of T cell immunity, Nat. Immunol. 1 (November (5)) (2000) 433–440.

[160] T.F. Rowley, A. Al-Shamkhani, Stimulation by soluble CD70 promotes strong primary and secondary CD8+ cytotoxic T cell responses in vivo, J. Immunol. 172 (May  (10))  (2004)  6039–6046.

[161] A. Schildknecht, I. Miescher, H. Yagita, M. van den Broek, Priming of CD8+ T cell responses by pathogens typically depends on CD70-mediated interactions with dendritic cells, Eur. J. Immunol. 37 (March (3)) (2007) 716–728 (WILEY-VCH Verlag).

[162] V. Peperzak, Veraar Eam, Y. Xiao, N. Babala, K. Thiadens, M. Brugmans, et al., CD8+ T cells produce the chemokine CXCL10 in response to CD27/CD70 costimulation to promote generation of the CD8+ effector T cell pool, J. Immunol. Am. Assoc. Immunol. 191 (Sep (6)) (2013) 3025–3036.

[163] Y. Xiao, V. Peperzak, A.M. Keller, J. Borst, CD27 instructs CD4+ T cells to provide help for the memory CD8+ T cell response after protein immunization, J. Immunol. 181 (July (2)) (2008) 1071–1082.

[164] H. Soares, H. Waechter, N. Glaichenhaus, E. Mougneau, H. Yagita, O. Mizenina, et al., A subset of dendritic cells induces CD4+ T cells to produce IFN-gamma by an IL-12-independent but CD70-dependent mechanism in vivo, J. Exp. Med. 204 (May (5)) (2007) (1095-106 Rockefeller University Press;).

[165] S. Feau, Z. Garcia, R. Arens, H. Yagita, J. Borst, S.P. Schoenberger, The CD4? T-cell help signal is transmitted from APC to CD8? T-cells via CD27-CD70 interactions, Nat. Commun. 10 (July (3)) (2012) 948 (Nature Publishing Group).

[166] A.M. Keller, Y. Xiao, V. Peperzak, S.H. Naik, J. Borst, Costimulatory ligand CD70 allows induction of CD8+ T-cell immunity by immature dendritic cells in a vaccination setting, Blood Am. Soc. Hematol. 113 (May (21)) (2009) 5167–5175.

[167] S.M. Lens, K. Tesselaar, M.H. van Oers, R.A. Van Lier, Control of lymphocyte function through CD27-CD70 interactions, Semin. Immunol. 10 (December(6)) (1998)   491–499.

[168] Y. Xiao, J. Hendriks, P. Langerak, H. Jacobs, J. Borst, CD27 is acquired by primed B cells at the centroblast stage and promotes germinal center formation, J. Immunol. 172 (June (12)) (2004) 7432–7441.

[169] M. Vossen Mtm Matmati, P.A. Hertoghs Kml Baars, M.-R. Gent, G. Leclercq, et al., CD27 de?nes phenotypically and functionally di?erent human NK cell subsets, J. Immunol. 180 (March (6)) (2008) 3739–3745.

[170] K. Takeda, H. Oshima, Y. Hayakawa, H. Akiba, M. Atsuta, T. Kobata, et al., CD27mediated activation of murine NK cells, J. Immunol. 164 (Febuary (4)) (2000) 1741–1745.

[171]  T. Sakanishi, H. Yagita, Anti-tumor effects of depleting and non-depleting antiCD27 monoclonal antibodies in immune-competent mice, Biochem. Biophys. Res. Commun.  393  (March  (4))  (2010)  829–835.

[172]  J.M. Kelly, P.K. Darcy, J.L. Markby, D.I. Godfrey, K. Takeda, H. Yagita, et al., Induction of tumor-specific T cell memory by NK cell-mediated tumor rejection, Nat. Immunol.  3 (January  (1)) (2002)  83–90.

[173] A.M. Keller, A. Schildknecht, Y. Xiao, M. van den Broek, J. Borst, Expression of costimulatory ligand CD70 on steady-state dendritic cells breaks CD8+ T cell tolerance and permits effective immunity, Immunity 29 (December (6)) (2008)  934–946 Elsevier.

[174]  R. Arens, K. Schepers, M.A. Nolte, M.F. van Oosterwijk, Raw. Van Lier, Tnm. Schumacher, et al., Tumor rejection induced by CD70-mediated quantitative and qualitative effects on effector CD8+ T cell formation, J. Exp. Med. 199 (Jun (11))  (2004)  1595–1605.

[175]  R.R. French, V.Y. Taraban, G.R. Crowther, T.F. Rowley, J.C. Gray, P.W. Johnson, et al., Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation, Blood Am. Soc. Hematol.  109  (June  (11))  (2007)  4810–4815.

[176] D.J. Roberts, N.A. Franklin, L.M. Kingeter, H. Yagita, A.L. Tutt, M.J. Glennie, et al., Control of established melanoma by CD27 stimulation is associated with enhanced effector function and persistence, and reduced PD-1 expression of tumor infiltrating CD8(+) T cells, J. Immunother. 33 (October (8)) (2010) 769–779.

[177]  L.A. Vitale, L.-Z. He, L.J. Thomas, J. Widger, J. Weidlick, A. Crocker, et al., Development of a human monoclonal antibody for potential therapy of CD27expressing lymphoma and leukemia, Clin. Cancer Res. Am. Assoc. Cancer Res. 18 (July (14)) (2012) 3812–3821.

[178] L.-Z. He, N. Prostak, L.J. Thomas, L. Vitale, J. Weidlick, A. Crocker, et al., Agonist anti-human CD27 monoclonal antibody induces T cell activation and tumor immunity in human CD27-transgenic mice, J. Immunol. Am. Assoc. Immunol. 119 (October (8)) (2013) 4174–4183.

[179]  L.-Z. He, L.J. Thomas, J. Testa, J. Weidlick, C. Sisson, R. Hammond, et al., Combination therapies augment the anti-tumor activity of agonist CD27 mAb in human CD27 transgenic mouse models, J. Immunother. Cancer BioMed. Cent. 1 (November (1)) (2013) P76.

[180] H.A. Burris, J.R. Infante, S.M. Ansell, J.J. Nemunaitis, G.R. Weiss, V.M. Villalobos, et al., Safety and activity of varlilumab, a novel and ?rst-in-Class agonist antiCD27 antibody, in patients with advanced solid tumors, J. Clin. Oncol. 35 (June (18))  (2017)  2028–2036.

[181] S. Ansell, D. Northfelt, I. Flinn, H. Burris, S. Dinner, V. Villalobos, et al., A phase I study of an agonist anti-CD27 human antibody (CDX-1127) in patients with advanced hematologic malignancies or solid tumors, J. Immunother. Cancer BioMed. Cent. 1 (Suppl 1) (2013) P259.

[182]  T.K. Owonikoko, A. Hussain, W.M. Stadler, D.C. Smith, H. Kluger, A.M. Molina, et al., First-in-human multicenter phase I study of BMS-936561 (MDX-1203), an antibody-drug conjugate targeting CD70, Cancer Chemother. Pharmacol. 77 (January  (1))  (2016)  155–162  (Springer  Berlin  Heidelberg).

[183] D. Coe, S. Begom, C. Addey, M. White, J. Dyson, Chai J-G: Depletion of regulatory T cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy, Cancer Immunol. Immunother. 59 (September (9)) (2010) 1367–1377.

[184]  K. Aida, R. Miyakawa, K. Suzuki, K. Narumi, T. Udagawa, Y. Yamamoto, et al., Suppression of Tregs by anti-glucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferon-a gene therapy for pancreatic cancer, Cancer  Sci.  105  (Febuary  (2))  (2014)  159–167.

[185] D.A. Knee, B. Hewes, J.L. Brogdon, Rationale for anti-GITR cancer immunotherapy, Eur. J. Cancer 67 (November) (2016) 1–10 (Elsevier).

[186]  F. Duan, Y. Lin, C. Liu, M.E. Engelhorn, A.D. Cohen, M. Curran, et al., Immune rejection of mouse tumors expressing mutated self, Clin. Cancer Res. 69 (April (8)) (2009)     3545–3553.

[187] P. Zhou, J. Qiu, L. L’Italien, D. Gu, D. Hodges, C.-C. Chao, B. et al. Mature, cells are critical to T-cell-mediated tumor immunity induced by an agonist anti-GITR monoclonal antibody, J. Immunother. 33 (October (8)) (2010) 789–797.

[188] L. Lu, X. Xu, B. Zhang, R. Zhang, H. Ji, X. Wang, Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs, J. Transl. Med. BioMed. Cent. 12 (Febuary (1)) (2014) 36.

[189] N. Yu, S. Fu, Z. Xu, Y. Liu, J. Hao, A. Zhang, et al., Synergistic antitumor responses by combined GITR activation and sunitinib in metastatic renal cell carcinoma, Int. J. Cancer 138 (January (2)) (2016) 451–462.

[190]  I.-K. Kim, B.-S. Kim, C.-H. Koh, J.-W. Seok, J.-S. Park, K.-S. Shin, et al., Glucocorticoid-induced tumor necrosis factor receptor-related protein co-stimulation facilitates tumor regression by inducing IL-9-producing helper T cells, Nat. Med.  21  (September(9))  (2015)  1010–1017.

[191]  L.X. Zhu, M. Davoodi, M.K. Srivastava, P. Kachroo, J.M. Lee, M. St John, et al., GITR agonist enhances vaccination responses in lung cancer, Oncoimmunology 4 (April  (4))  (2015)  e992237  (Taylor & Francis).

[192] N.D. Brunn, S. Mauze, D. Gu, D. Wiswell, R. Ueda, D. Hodges, et al., The role of anti-Drug antibodies in the pharmacokinetics, disposition, target engagement, and efficacy of a GITR agonist monoclonal antibody in mice, J. Pharmacol. Exp. Ther. 356 (March (3)) (2016) 574–586.

[193]  R. Leyland, A. Watkins, K.A. Mulgrew, N. Holoweckyj, L. Bamber, N.J. Tigue, et al., A novel murine gitr ligand fusion protein induces antitumor activity as a monotherapy that is further enhanced in combination with an OX40 agonist, Clin. Cancer Res. 23 (July (13)) (2017) 3416–3427.

[194] N.J. Tigue, L. Bamber, J. Andrews, S. Ireland, J. Hair, E. Carter, et al., MEDI1873, a potent, stabilized hexameric agonist of human GITR with regulatory T-cell targeting potential, Oncoimmunology 6 (3) (2017) e1280645 (Taylor & Francis).

[195]  W.-C. Chang, C.-H. Li, S.-C. Huang, D.-Y. Chang, L.-Y. Chou, C. Sheu B-, Clinical signi?cance of regulatory T cells and CD8+ effector populations in patients with human  endometrial  carcinoma,  Cancer  116  (December  (24))  (2010)  5777–5788 (Wiley Subscription Services, Inc., A Wiley Company).

[196] L.T. Krausz, E. Fischer-Fodor, Z.Z. Major, B. Fetica, GITR-expressing regulatory Tcell subsets are increased in tumor-positive lymph nodes from advanced breast cancer patients as compared to tumor-negative lymph nodes, Int. J. Immunopathol. Pharmacol. 25 (January (1)) (2012) 59–66 (SAGE PublicationsSage UK: London, England).

[197]  C.-H. Li, W.-H. Kuo, W.-C. Chang, S.-C. Huang, K.-J. Chang, B.-C. Sheu, Activation of regulatory T cells instigates functional down-regulation of cytotoxic T lymphocytes in human breast cancer, Immunol. Res. 51 (October (1)) (2011) 71–79.

[198]  Padovani Ctj, C.M. Bonin, I.A. Tozetti, Ferreira Amt, C.E.D.S. Fernandes, I.P.D. Costa, Glucocorticoid-induced tumor necrosis factor receptor expression in patients with cervical human papillomavirus infection, Rev. Soc. Bras. Med. Trop. 46  (May  (3))  (2013)  288–292  (1st  ed.  SBMT).

[199]  A. Pedroza-Gonzalez, G. Zhou, S.P. Singh, P.P. Boor, Q. Pan, D. Grunhagen, et al., GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cells ex vivo, Oncoimmunology 4 (December (12)) (2015) e1051297 (Taylor & Francis).

[200] E.J. Brown, W.A. Frazier, Integrin-associated protein (CD47) and its ligands, Trends Cell Biol. 11 (March (3)) (2001) 130–135.

[201] E. Brown, L. Hooper, T. Ho, H. Gresham, Integrin-associated protein: a 50-kD plasma membrane antigen physically and functionally associated with integrins, J. Cell Biol. 111 (December 6 Pt 1) (1990) 2785–2794 (The Rockefeller University Press).

[202] F.P. Lindberg, Molecular cloning of integrin-associated protein: an immunoglobulin family member with multiple membrane-spanning domains implicated in alpha v beta 3-dependent ligand binding, J. Cell Biol. 123 (October (2)) (1993)   485–496.

[203]  X.Q. Wang, W.A. Frazier, The thrombospondin receptor CD47 (IAP) modulates and associates with alpha2 beta1 integrin in vascular smooth muscle cells, Mol. Biol. Cell Am. Soc. Cell Biol. 9 (April (4)) (1998) 865–874.

[204] M.I. Reinhold, F.P. Lindberg, D. Plas, S. Reynolds, M.G. Peters, E.J. Brown, In vivo expression of alternatively spliced forms of integrin-associated protein (CD47), J. Cell Sci. 108 (November pt 11) (1995) 3419–3425.

[205]  P.A. Oldenborg, A. Zheleznyak, Y.F. Fang, C.F. Lagenaur, H.D. Gresham, F.P. Lindberg, Role of CD47 as a marker of self on red blood cells, Science 288 (June  (5473))  (2000)  2051–2054.

[206] L. Fossati-Jimack, S. Azeredo da Silveira, T. Moll, T. Kina, F.A. Kuypers, P. A. Oldenborg, et al., Selective increase of autoimmune epitope expression on aged erythrocytes in mice: implications in anti-erythrocyte autoimmune responses, J. Autoimmun. 18 (Febuary (1)) (2002) 17–25.

[207]  S. Khandelwal, N. van Rooijen, R.K. Saxena, Reduced expression of CD47 during murine red blood cell (RBC) senescence and its role in RBC clearance from the circulation,  Transfusion  (Paris) 47  (September (9)) (2007)  1725–1732  (Blackwell Publishing Inc;).

[208] M. Olsson, A. Nilsson, P.-A. Oldenborg, Dose-dependent inhibitory effect of CD47 in macrophage uptake of IgG-opsonized murine erythrocytes, Biochem. Biophys. Res.  Commun.  352  (January  (1))  (2007)  193–197.

[209] T. Ishikawa-Sekigami, Y. Kaneko, H. Okazawa, T. Tomizawa, J. Okajo, Y. Saito, et al., SHPS-1 promotes the survival of circulating erythrocytes through inhibition of phagocytosis by splenic macrophages, Blood Am. Soc. Hematol. 107 (January (1))  (2006)  341–348.

[210] T. Yamao, T. Noguchi, O. Takeuchi, U. Nishiyama, H. Morita, T. Hagiwara, et al., Negative regulation of platelet clearance and of the macrophage phagocytic response by the transmembrane glycoprotein SHPS-1, J. Biol. Chem. 277 (October (42)) (2002) 39833–39839.

[211]  Y. Fujioka, T. Matozaki, T. Noguchi, A. Iwamatsu, T. Yamao, N. Takahashi, et al., A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion, Mol Cell Biol. Am. Soc. Microbiol. (ASM). 16 (December (12)) (1996) 6887–6899.

[212] R.K. Tsai, D.E. Discher, Inhibition of self engulfment through deactivation of myosin-II at the phagocytic synapse between human cells, J. Cell Biol. 180 (March (5)) (2008) 989–1003 (Rockefeller University Press).

[213] E.M. van Beek, J.A. Zarate, R. van Bruggen, K. Schornagel, Tool Atj, T. Matozaki, et al., SIRPα controls the activity of the phagocyte NADPH oxidase by restricting the expression of gp91(phox), Cell Rep. 2 (4) (2012) 748–755 (Elsevier).

[214] Lesage S Van VQ, S. Bouguermouh, P. Gautier, M. Rubio, M. Levesque, et al., Expression of the self-marker CD47 on dendritic cells governs their tra?cking to secondary lymphoid organs, EMBO J. 25 (November (23)) (2006) 5560–5580 EMBO Press.

[215]  P. Grimbert, S. Bouguermouh, N. Baba, T. Nakajima, Z. Allakhverdi, D. Braun, et al., Thrombospondin/CD47 interaction: a pathway to generate regulatory T cells from human CD4+ CD25T cells in response to in?ammation, J. Immunol. 177 (September (6)) (2006) 3534–3541.

[216]  J.M. Baumgartner, B.E. Palmer, A. Banerjee, Role of melanoma secreted thrombospondin-1 on induction of immunosuppressive regulatory T cells through CD47, J. Cancer (2008).

[217] M.N. Avice, M. Rubio, M. Sergerie, G. Delespesse, M. Sarfati, CD47 ligation selectively inhibits the development of human naive T cells into Th1 effectors, J.  Immunol. 165 (October (8)) (2000) 4624–4631.

[218] P.P. Manna, W.A. Frazier, CD47 mediates killing of breast tumor cells via Gi-dependent inhibition of protein kinase A, Clin. Cancer Res. 64 (February (3)) (2004) 1026–1036  (Feb  1).

[219] J.M. Rendtlew Danielsen, L.M. Knudsen, I.M. Dahl, M. Lodahl, T. Rasmussen, Dysregulation of CD47 and the ligands thrombospondin 1 and 2 in multiple myeloma, Br. J. Haematol. 138 (September (6)) (2007) 756–760 (Blackwell Publishing Ltd).

[220]  M.J. Kim, J.-C. Lee, J.-J. Lee, S. Kim, S.G. Lee, Park S-W, et al: association of CD47 with natural killer cell-mediated cytotoxicity of head-and-neck squamous cell carcinoma lines, Tumour Biol. 29 (1) (2008) 28–34 (Karger Publishers).

[221]  S. Jaiswal, Jamieson Chm, W.W. Pang, C.Y. Park, M.P. Chao, R. Majeti, et al., CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis, Cell  138  (July (2))  (2009) 271–285 (Elsevier).

[222]  K.S. Chan, I. Espinosa, M. Chao, D. Wong, L. Ailles, M. Diehn, et al., Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells, Proc. Natl. Acad. Sci. U. S. A. 106 (August (33)) (2009)     14016–14021.

[223] M.P. Chao, A.A. Alizadeh, C. Tang, J.H. Myklebust, B. Varghese, S. Gill, et al., AntiCD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma, Cell 142 (September (5)) (2010) 699–713 (Elsevier).

[224] B. Edris, K. Weiskopf, A.K. Volkmer, J.-P. Volkmer, S.B. Willingham, H. ContrerasTrujillo, et al., Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma, Proc. Natl. Acad. Sci. U. S. A. 109 (April (17))   (2012)   6656–6661.

[225]  S.B. Willingham, J.-P. Volkmer, A.J. Gentles, D. Sahoo, P. Dalerba, S.S. Mitra, et al., The CD47-signal regulatory protein alpha (SIRPα) interaction is a therapeutic target for human solid tumors, Proc. Natl. Acad. Sci. U. S. A. 109 (April (7))  (2012)  6662–6667.

[226] R. Majeti, M.P. Chao, A.A. Alizadeh, W.W. Pang, S. Jaiswal, K.D. Gibbs, et al., CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells, Cell 138 (July (2)) (2009) 286–299 Elsevier.

[227] R.W. Tothill, A.V. Tinker, J. George, R. Brown, S.B. Fox, S. Lade, et al., Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome, Clin. Cancer Res. 14 (August (16)) (2008) 5198–5208.

[228] C.H. Chung, J.S. Parker, G. Karaca, J. Wu, W.K. Funkhouser, D. Moore, et al., Molecular classi?cation of head and neck squamous cell carcinomas using patterns of gene expression, Cancer Cell. 5 (May (5)) (2004) 489–500.

[229] O. Gravendeel Lam Kouwenhoven Mcm Gevaert, J.J. de Rooi, A.P. Stubbs, J.E. Duijm, et al., Intrinsic gene expression pro?les of gliomas are a better predictor of survival than histology, Clin. Cancer Res. 69 (December (23)) (2009) 9065–9072.

[230]  C.L. Nutt, D.R. Mani, R.A. Betensky, P. Tamayo, J.G. Cairncross, C. Ladd, et al., Gene expression-based classi?cation of malignant gliomas correlates better with survival than histological classi?cation, Clin. Cancer Res. 63 (April (7)) (2003) 1602–1607.

[231] W.A. Freije, F.E. Castro-Vargas, Z. Fang, S. Horvath, T. Cloughesy, L.M. Liau, et al., Gene expression pro?ling of gliomas strongly predicts survival, Clin. Cancer Res. Am. Assoc. Cancer Res. 64 (September (18)) (2004) 6503–6510.

[232] Y. Lee, A.C. Scheck, T.F. Cloughesy, A. Lai, J. Dong, H.K. Farooqi, et al., Gene expression analysis of glioblastomas identifies the major molecular basis for the prognostic bene?t of younger age, BMC Med. Genomics BioMed Cent. 1 (October (1))  (2008)  52.

[233]  J.J. Smith, N.G. Deane, F. Wu, N.B. Merchant, B. Zhang, A. Jiang, et al., Experimentally derived metastasis gene expression pro?le predicts recurrence and death in patients with colon cancer, Gastroenterology 138 (March (3)) (2010) 958–968 (Elsevier).

[234]  Z. Xiao, H. Chung, B. Banan, P.T. Manning, K.C. Ott, S. Lin, et al., Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma,  Cancer  Lett. 360 (May (2))  (2015) 302–309 (Elsevier).

[235] J. Liu, L. Wang, F. Zhao, S. Tseng, C. Narayanan, L. Shura, et al., Pre-Clinical development of a humanized anti-CD47 antibody with anti-Cancer therapeutic potential, PLoS One 10 (9) (2015) e0137345 (KD Bunting).

[236]  K. Takenaka, T.K. Prasolava, S.M. Wang Jcy Mortin-Toth, S. Khalouei, O.I. Gan, et al., Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells, Nat. Immunol. 8 (December (12)) (2007)  1313–1323.

[237]  T. Yamauchi, K. Takenaka, S. Urata, T. Shima, Y. Kikushige, T. Tokuyama, et al., Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve e?cient human cell engraftment, Blood Am. Soc. Hematol. 121 (Febuary  (8))   (2013)   1316–1325.

[238] X. Liu, Y. Pu, K. Cron, L. Deng, J. Kline, W.A. Frazier, et al., CD47 blockade triggers T cell-mediated destruction of immunogenic tumors, Nat. Med. 21 (10) (2015 Oct) 1209–1215.

[239]  I. Thйate, N. van Baren, L. Pilotte, P. Moulin, P. Larrieu, J.-C. Renauld, et al., Extensive pro?ling of the expression of the indoleamine 2, 3-dioxygenase 1 protein in normal and tumoral human tissues, Cancer Immunol. Res. Am. Assoc. Cancer Res.  3  (Febuary  (2))  (2015)  161–172.

[240] Y. Kudo, I. Boyd Car Spyropoulou, O. Redman Cwg Takikawa, T. Katsuki, et al., Indoleamine 2,3-dioxygenase: distribution and function in the developing human placenta, J. Reprod. Immunol. 61 (April (2)) (2004) 87–98.

[241]  P. Ligam, U. Manuelpillai, E.M. Wallace, D. Walker, Localisation of indoleamine 2,3-dioxygenase and kynurenine hydroxylase in the human placenta and decidua: implications for role of the kynurenine pathway in pregnancy, Placenta 26 (July (6))   (2005)   498–504.

[242] D.H. Munn, M.D. Sharma, D. Hou, B. Baban, J.R. Lee, S.J. Antonia, et al., Expression of indoleamine 2, 3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes, J. Clin. Invest. Am. Soc. Clin. Invest. 114 (July (2)) (2004) 280–290.

[243]  K. Higuchi, O. Hayaishi, Enzymatic Formation OF D-KYNURENINE, (1963) (August 1).

[244] S. Yamamoto, O. Hayaishi, Tryptophan pyrrolase of rabbit intestine: dand Ltryptophan-cleaving enzyme or enzymes, J. Biol. Chem. 242 (November (22)) (1967)   5260–5266.

[245] O. Takikawa, R. Yoshida, R. Kido, O. Hayaishi, Tryptophan degradation in mice initiated by indoleamine 2, 3-dioxygenase, J. Biol. Chem. Am. Soc. Biochem. Mol. Biol. 261 (March (15)) (1986) 3648–3653.

[246] D.H. Munn, M. Zhou, J.T. Attwood, I. Bondarev, S.J. Conway, B. Marshall, et al., Prevention of allogeneic fetal rejection by tryptophan catabolism, Science 281 (August (5380)) (1998) 1191–1193.

[247] D.H. Munn, E. Sha?zadeh, J.T. Attwood, I. Bondarev, A. Pashine, A.L. Mellor, Inhibition of T cell proliferation by macrophage tryptophan catabolism, J. Exp. Med. 189 (May (9)) (1999) 1363–1372 (The Rockefeller University Press).

[248] A.L. Mellor, D.B. Keskin, T. Johnson, P. Chandler, D.H. Munn, Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses, J. Immunol. 168 (April (8)) (2002)   3771–3776.

[249]  F. Fallarino, U. Grohmann, C. Vacca, C. Orabona, A. Spreca, M.C. Fioretti, et al., T cell apoptosis by kynurenines, Adv. Exp. Med. Biol. 527 (2003) 183–190.

[250] Y. Yan, G.-X. Zhang, B. Gran, F. Fallarino, S. Yu, H. Li, et al., IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis, J. Immunol. Am. Assoc. Immunol. 185 (November (10)) (2010) 5953–5961.

[251] F. Yamazaki, T. Kuroiwa, O. Takikawa, R. Kido, Human indolylamine 2, 3-dioxygenase. Its tissue distribution, and characterization of the placental enzyme, Biochem. J 230 (September (3)) (1985) 635–638 (Portland Press Ltd).

[252]  C. Uyttenhove, L. Pilotte, I. Thйate, V. Stroobant, D. Colau, N. Parmentier, et al., Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2, 3-dioxygenase, Nat. Med. 9 (October (10)) (2003) 1269–1274 (Nature Publishing Group).

[253] M. Friberg, R. Jennings, M. Alsarraj, S. Dessureault, A. Cantor, M. Extermann, et al., Indoleamine 2, 3-dioxygenase contributes to tumor cell evasion of T cellmediated rejection, Int. J. Cancer 101 (September (2)) (2002) 151–155 (Wiley Subscription Services, Inc., A Wiley Compan).

[254]  D.A. Wainwright, A.L. Chang, M. Dey, I.V. Balyasnikova, C.K. Kim, A. Tobias, et al., Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors, Clin. Cancer Res. 20 (October (20)) (2014)     5290–5301.

[255] M.Y. Chang, J. Boulden, E. Sutanto-Ward, J.B. Duhadaway, A.P. Soler, A.J. Muller, et al., Bin1 ablation in mammary gland delays tissue remodeling and drives cancer progression, Clin. Cancer Res. 67 (January (1)) (2007) 100–107.

[256] K. Ge, F. Minhas, J. Duhadaway, N.C. Mao, D. Wilson, R. Buccafusca, et al., Loss of heterozygosity and tumor suppressor activity of Bin1 in prostate carcinoma, Int. J. Cancer 86 (April (2)) (2000) 155–161.

[257]  M.Y. Chang, J. Boulden, J.B. Katz, L. Wang, T.J. Meyer, A.P. Soler, et al., Bin1 ablation increases susceptibility to cancer during aging, particularly lung cancer, Clini. Cancer Res. Am. Assoc. Cancer Res. 67 (August (16)) (2007) 7605–7612.

[258]  T. Tajiri, X. Liu, P.M. Thompson, S. Tanaka, S. Suita, H. Zhao, et al., Expression of a MYCN-interacting isoform of the tumor suppressor BIN1 is reduced in neuroblastomas with unfavorable biological features, Clin. Cancer Res. 9 (August (9)) (2003)     3345–3355.

[259] K. Ge, J. Duhadaway, W. Du, M. Herlyn, U. Rodeck, G.C. Prendergast, Mechanism for elimination of a tumor suppressor: aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma, Proc. Natl. Acad. Sci. 96 (August (17))  (1999)  9689–9694.

[260]  A.J. Muller, J.B. Duhadaway, P.S. Donover, E. Sutanto-Ward, G.C. Prendergast, Inhibition of indoleamine 2, 3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy, Nat. Med. 11 (March (3)) (2005) 312–319 (Nature Publishing Group).

[261]  G.L. Beatty, P.J. O’Dwyer, J. Clark, J.G. Shi, K.J. Bowman, P.A. Scherle, I. et al. First-in-Human Phase, Study of the oral inhibitor of indoleamine 2,3-Dioxygenase1 epacadostat (INCB024360) in patients with advanced solid malignancies, Clin. Cancer Res. 23 (July (13)) (2017) 3269–3276.

[262] T.C. Gangadhar, O. Hamid, D.C. Smith, T.M. Bauer, J.S. Wasser, J.J. Luke, et al., Preliminary results from a Phase I/II study of epacadostat (incb024360) in combination with pembrolizumab in patients with selected advanced cancers, J. Immunother. Cancer BioMed. Cent. 3 (November (2)) (2015) O7.

[263]  A.R. Manser, S. Weinhold, M. Uhrberg, Human Kir repertoires: shaped by genetic diversity and evolution, Immunol. Rev. 267 (September (1)) (2015) 178–196.

[264]  M.M. Tu, A.B. Mahmoud, A. Wight, A. Mottashed, S. Bйlanger, Rahim Mma, et al., Ly49 family receptors are required for cancer immunosurveillance mediated by natural killer cells, Clin. Cancer Res. Am. Assoc. Cancer Res. 74 (14) (2014) 3684–3694   (Jul   15).

[265]  M.M. Tu, A.B. Mahmoud, A.P. Makrigiannis, Licensed and unlicensed NK cells: di?erential roles in cancer and viral control, Front. Immunol. Front. 7 (2016) 166.

[266]  S. Kulkarni, M.P. Martin, M. Carrington, The Yin and Yang of HLA and KIR in human disease, Semin. Immunol. 20 (December (6)) (2008) 343–352.

[267]  S. Setrakian, B.O. Saunders, S.V. Nicosia, Isolation and characterization of rabbit peritoneal mesothelial cells, Acta Cytol. 34 (January (1)) (1990) 92–100.

[268]  A. Wisniewski, R. Jankowska, E. Passowicz-Muszynska, E. Wisniewska, E. Majorczyk, I. Nowak, et al., KIR2DL2/S2 and HLA-C C1C1 genotype is associated with better response to treatment and prolonged survival of patients with non-small cell lung cancer in a Polish Caucasian population, Hum. Immunol. 73 (9)   (2012)   927–931.

[269]  P. Portela, L.F. Jobim, P.H. Salim, W.J. Ko?, T.J. Wilson, M.R. Jobim, et al., Analysis of KIR gene frequencies and HLA class I genotypes in prostate cancer and control group, Int. J. Immunogenet. 39 (October (5)) (2012) 423–428 (Blackwell Publishing Ltd).

[270] A. Vuletic, V. Juriљic, I. Jovanic, Z. Milovanovic, S. Nikolic, G. Konjevic, Distribution of several activating and inhibitory receptors on CD3(?)CD56(+) NK cells in regional lymph nodes of melanoma patients, J. Surg. Res. 183 (August (2)) (2013) 860–868 (Elsevier).

[271] M.R. Jobim, M. Jobim, P.H. Salim, P. Portela, L.F. Jobim, S. Leistner-Segal, et al., Analysis of KIR gene frequencies and HLA class I genotypes in breast cancer and control group, Hum. Immunol. 74 (September (9)) (2013) 1130–1133.

[272] A. Dutta, N. Saikia, J. Phookan, M.N. Baruah, S. Baruah, Association of killer cell immunoglobulin-like receptor gene 2DL1 and its HLA-C2 ligand with family history of cancer in oral squamous cell carcinoma, Immunogenetics 66 (August (7–8)) (2014) 439–448 (7 ed. Springer Berlin Heidelberg).

[273] S. Giebel, A. Boratyn-Nowicka, L. Karabon, A. Jedynak, J. Pamula-Pilat, K. Tecza, et al., Associations between genes for killer immunoglobulin-like receptors and their ligands in patients with epithelial ovarian cancer, Hum. Immunol. 75 (June (6))  (2014)  508–513.

[274] K. Beksac, M. Beksac, K. Dalva, E. Karaagaoglu, M.B. Tirnaksiz, Impact of killer immunoglobulin-Like Receptor/Ligand genotypes on outcome following surgery among patients with colorectal cancer: activating KIRs are associated with longTerm disease free survival, PLoS One 10 (7) (2015) e0132526 V. De Re.

[275]  W. Wang, A.K. Erbe, M. Gallenberger, K. Kim, L. Carmichael, D. Hess, et al., Killer immunoglobulin-like receptor (KIR) and KIR-ligand genotype do not correlate with clinical outcome of renal cell carcinoma patients receiving high-dose IL2, Cancer Immunol. Immunother. 65 (12) (2016) 1523–1532 (Springer Berlin Heidelberg).

[276]  M. Dominguez-Valentin, A. Gras Navarro, A.M. Rahman, S. Kumar, C. Retiиre, E. Ulvestad, et al., Identification of a natural killer cell receptor allele that prolongs survival of cytomegalovirus-Positive glioblastoma patients, Clin. Cancer Res. 76  (September  (18))  (2016)  5326–5336.

[277]  S. Omar Al, D. Middleton, E. Marshall, D. Porter, G. Xinarianos, O. Raji, et al., Associations between genes for killer immunoglobulin-like receptors and their ligands in patients with solid tumors, Hum. Immunol. 71 (October (10)) (2010) 976–981.

[278]  E. Wang, L.-C. Wang, C.-Y. Tsai, V. Bhoj, Z. Gershenson, E. Moon, et al., Generation of potent T-cell immunotherapy for cancer using DAP12-Based, multichain, chimeric immunoreceptors, Cancer Immunol. Res. 3 (July (7)) (2015 Jul) 815–826.

[279] K. Tцpfer, M. Cartellieri, S. Michen, R. Wiedemuth, N. Mьller, D. Lindemann, et al., DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy, J. Immunol. Am. Assoc. Immunol. 194 (April (7)) (2015) 3201–3212.

[280] F. Romagnй, P. Andrй, P. Spee, S. Zahn, N. Anfossi, L. Gauthier, et al., Preclinical characterization of 1–7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells, Blood Am. Soc. Hematol. 114 (September (13)) (2009) 2667–2677.

[281]  M. Carlsten, N. Korde, R. Kotecha, R. Reger, S. Bor, D. Kazandjian, et al., Checkpoint inhibition of KIR2D with the monoclonal antibody IPH2101 induces contraction and hyporesponsiveness of NK cells in patients with myeloma, Clin. Cancer Res. Am. Assoc. Cancer Res. 22 (November (21)) (2016) 5211–5222.

[282] R. Leidner, H. Kang, R. Haddad, N.H. Segal, L.J. Wirth, R.L. Ferris, et al., Abstract 05: O5 Preliminary efficacy from a phase I/II study of the natural killer cell?targeted antibody lirilumab in combination with nivolumab in squamous cell carcinoma of the head and neck, J. Immunother. Cancer 4 (suppl 2) (2017) 91.

[283] G. Pittari, P. Filippini, G. Gentilcore, J.-C. Grivel, S. Rutella, Revving up natural killer cells and cytokine-Induced killer cells against hematological malignancies, Front Immunol. Front. 6 (2) (2015) 230.

[284]  A. Muntasell, M.C. Ochoa, L. Cordeiro, P. Berraondo, A. Lуpez-Dнaz de Cerio, M. Cabo, et al., Targeting NK-cell checkpoints for cancer immunotherapy, Curr. Opin. Immunol. 45 (April) (2017) 73–81.

[285]  L. Cifaldi, P. Romania, M. Falco, S. Lorenzi, R. Meazza, S. Petrini, et al., ERAP1 regulates natural killer cell function by controlling the engagement of inhibitory receptors, Clin. Cancer Res. 75 (March (5)) (2015) 824–834.

[286]  E.M. Levy, G. Sycz, J.M. Arriaga, M.M. Barrio, E.M. Euw von, S.B. Morales, et al., Cetuximab-mediated cellular cytotoxicity is inhibited by HLA-E membrane expression in colon cancer cells, Innate Immun. 15 (April (2)) (2009) 91–100 (SAGE  PublicationsSage UK: London, England).

[287]  M. Gooden, M. Lampen, E.S. Jordanova, N. Le?ers, J.B. Trimbos, S.H. van der Burg, et al., Hla-E expression by gynecological cancers restrains tumor-infiltrating CD8? T lymphocytes, Proc. Natl. Acad. Sci. U. S. A. 108 (June (26)) (2011) 10656–10661.

[288] C. Bossard, S. Bйzieau, T. Matysiak-Budnik, C. Volteau, C.L. Laboisse, F. Jotereau, et al., HLA-E/й2 microglobulin overexpression in colorectal cancer is associated with recruitment of inhibitory immune cells and tumor progression, Int. J. Cancer 131 (August (4)) (2012) 855–863 (Wiley Subscription Services, Inc., A Wiley Company).

[289] C. Sun, J. Xu, Q. Huang, M. Huang, H. Wen, C. Zhang, et al., High NKA expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer, Oncoimmunology 264562 (2017) G2.

[290] C. Guillerey, N.D. Huntington, M.J. Smyth, Targeting natural killer cells in cancer immunotherapy, Nat. Immunol. 17 (August (9)) (2016) 1025–1036.

[291]  F. Katou, H. Ohtani, Y. Watanabe, T. Nakayama, O. Yoshie, K. Hashimoto, Di?ering phenotypes between intraepithelial and stromal lymphocytes in earlystage tongue cancer, Clin. Cancer Res. 67 (December (23)) (2007) 11195–111201.

[292] E. Pace, C. Di Sano, M. Ferraro, A. Tipa, D. Olivieri, M. Spatafora, et al., Altered CD94/NKG2A and perforin expression reduce the cytotoxic activity in malignant pleural e?usions, Eur. J. Cancer 47 (January (2)) (2011) 296–304 Elsevier.

[293]  M. Gillard-Bocquet, C. Caer, N. Cagnard, L. Crozet, M. Perez, W.H. Fridman, et al., Lung tumor microenvironment induces specific gene expression signature in intratumoral NK cells, Front Immunol. Front. 4 (2013) 19.

[294]  S. Jin, Y. Deng, J.-W. Hao, Y. Li, B. Liu, Y. Yu, et al., NK cell phenotypic modulation in lung cancer environment, PLoS One 9 (10) (2014) e109976 X.-Y. Guan.

[295] W.-C. Chang, C.-H. Li, L.-H. Chu, P.-S. Huang, B.-C. Sheu, Huang S-C. Regulatory, T cells suppress natural killer cell immunity in patients with human cervical carcinoma, Int. J. Gynecol. Cancer 26 (January (1)) (2016) 156–162.

[296]  E. Cariani, M. Pilli, V. Barili, E. Porro, E. Biasini, A. Olivani, et al., Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments, Oncoimmunology 5 (August (8)) (2016) e1154249.

[297] Y.S. Rocca, M.P. Roberti, E.P. Juliб, M.B. Pampena, L. Bruno, S. Rivero, N.K. et al. Phenotypic Functional Dysregulated Blood, Cells in colorectal cancer patients can Be activated by cetuximab plus IL-2or IL-15, Front. Immunol. 7 (24) (2016) 413.

[298] A. Katona, A. Konrбdy, M. Marton, Cardiovascular symptoms in hyperthyroidism, Orv. Hetil. 110 (January(2)) (1969) 61–63.

[299]  R.S. Herbst, J.-C. Soria, M. Kowanetz, G.D. Fine, O. Hamid, M.S. Gordon, et al., Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients,  Nature  515  (November  (7528))  (2014)  563–567.