Douglas Hanahan, Robert A. Weinberg. Hallmarks of cancer: the next generation. Cell, Volume 144, Issue 5, p646–674, 4 March 2011
A second, still-unresolved issue surrounding tumor formation involves the role that the immune system plays in resisting or eradicating formation and progression of incipient neoplasias, late-stage tumors, and micrometastases. The long-standing theory of immune surveillance proposes that cells and tissues are constantly monitored by an ever-alert immune system, and that such immune surveillance is responsible for recognizing and eliminating the vast majority of incipient cancer cells and thus nascent tumors. According to this logic, solid tumors that do appear have somehow managed to avoid detection by the various arms of the immune system or have been able to limit the extent of immunological killing, thereby evading eradication.
The role of defective immunological monitoring of tumors would seem to be validated by the striking increases of certain cancers in immunocompromised individuals. However, the great majority of these are virus-induced cancers, suggesting that much of the control of this class of cancers normally depends on reducing viral burden in infected individuals, in part through eliminating virus-infected cells. These observations, therefore, seem to shed little light on the possible role of the immune system in limiting formation of the >80% of tumors of nonviral etiology. In recent years, however, an increasing body of evidence, both from genetically engineered mice and from clinical epidemiology, suggests that the immune system operates as a significant barrier to tumor formation and progression, at least in some forms of non-virus-induced cancer.
When mice genetically engineered to be deficient for various components of the immune system were assessed for the development of carcinogen-induced tumors, it was observed that tumors arose more frequently and/or grew more rapidly in the immunodeficient mice relative to immunocompetent controls. In particular, deficiencies in the development or function of CD8+ cytotoxic T lymphocytes (CTLs), CD4+ Th1 helper T cells, or natural killer (NK) cells each led to demonstrable increases in tumor incidence; moreover, mice with combined immunodeficiencies in both T cells and NK cells were even more susceptible to cancer development. The results indicated that, at least in certain experimental models, both the innate and adaptive cellular arms of the immune system are able to contribute significantly to immune surveillance and thus tumor eradication.
In addition, transplantation experiments have shown that cancer cells that originally arose in immunodeficient mice are often inefficient at initiating secondary tumors in syngeneic immunocompetent hosts, whereas cancer cells from tumors arising in immunocompetent mice are equally efficient at initiating transplanted tumors in both types of hosts. Such behavior has been interpreted as follows: Highly immunogenic cancer cell clones are routinely eliminated in immunocompetent hosts—a process that has been referred to as «immunoediting»—leaving behind only weakly immunogenic variants to grow and generate solid tumors; such weakly immunogenic cells can thereafter colonize both immunodeficient and immunocompetent hosts. Conversely, when arising in immunodeficient hosts, the immunogenic cancer cells are not selectively depleted and can, instead, prosper along with their weakly immunogenic counterparts. When cells from such nonedited tumors are serially transplanted into syngeneic recipients, the immunogenic cancer cells are rejected when they confront, for the first time, the competent immune systems of their secondary hosts. (Unanswered in these particular experiments is the question of whether the chemical carcinogens used to induce such tumors are prone to generate cancer cells that are especially immunogenic.)
Clinical epidemiology also increasingly supports the existence of antitumoral immune responses in some forms of human cancer. For example, patients with colon and ovarian tumors that are heavily infiltrated with CTLs and NK cells have a better prognosis than those that lack such abundant killer lymphocytes; the case for other cancers is suggestive but less compelling and is the subject of ongoing investigation. Additionally, some immunosuppressed organ transplant recipients have been observed to develop donor-derived cancers, suggesting that in the ostensibly tumor-free donors, the cancer cells were held in check, in a dormant state, by a fully functional immune system.
Still, the epidemiology of chronically immunosuppressed patients does not indicate significantly increased incidences of the major forms of nonviral human cancer, as noted above. This might be taken as an argument against the importance of immune surveillance as an effective barrier to tumorigenesis and tumor progression. We note, however, that HIV and pharmacologically immunosuppressed patients are predominantly immunodeficient in the T and B cell compartments and thus do not present with the multicomponent immunological deficiencies that have been produced in the genetically engineered mutant mice lacking both NK cells and CTLs; this leaves open the possibility that such patients still have residual capability for an immunological defense against cancer that is mounted by NK and other innate immune cells.
In truth, the above discussions of cancer immunology simplify tumor-host immunological interactions, as highly immunogenic cancer cells may well evade immune destruction by disabling components of the immune system that have been dispatched to eliminate them. For example, cancer cells may paralyze infiltrating CTLs and NK cells, by secreting TGF-β or other immunosuppressive factors. More subtle mechanisms operate through the recruitment of inflammatory cells that are actively immunosuppressive, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Both can suppress the actions of cytotoxic lymphocytes.
In light of these considerations and the still-rudimentary demonstrations of antitumor immunity as a significant barrier to tumor formation and progression in humans, we present immunoevasion as another emerging hallmark, whose generality as a core hallmark capability remains to be firmly established.