Resistance of cancer cells to CTL-mediated immunotherapyResistance to targeted anti-cancer therapeutics. Benjamin Bonavida, Salem Chouaib (Eds). Springer International Publishing Switzerland (2015)

According to the classical model of tumorigenesis, every cell of the body is equally susceptible to acquire an unlimited and uncontrolled proliferative potential, following genetic and epigenetic mutations. Clonal evolution of different subclones, dictated by environmental influences and continuing mutagenesis, explains the phenotypic differences observed in a tumor population [1]. Accumulating evidences suggest that tumor growth and progression are driven by a subset of cells with “stemness” properties, called cancer stem cells (CSCs). Located at the top of tumor hierarchy, these cells possess the long-life capacity to self-renew and generate the heterogeneous population of differentiated descendants, which constitute the tumor bulk [2]. The practical translation of this definition is their ability to generate a serially transplantable phenocopy of the original malignancy when injected into immuno-compromised mice [3].

From a clinical point of view, CSCs have been defined by multiple resistant mechanisms against anti-cancer therapies contributing to tumor recurrence and metastatic dissemination [4]. Similar to normal stem cells, CSCs were reported to shuttle between quiescence, slow-cycling and active states [5, 6]. Despite the loss of the CDK4/6 pathway regulation, the retention in a non-proliferating or G0 state, depends on the activation of p21 and p27 cell-cycle inhibitors, which block the transition from G1 to S-phase [7]. Interestingly, CSCs are stimulated to enter in a proliferative state in response to signals produced by the tumor microenvironment, such as the TGF-β family members which abrogate the p21 and p27 activation [8]. Although conventional cancer therapies are targeting the cell cycle and/or rapidly dividing cells, most patients relapse because of the quiescent regrowth of CSCs [9]. Complementary mechanisms responsible for chemoresistance are represented by high levels of anti-apoptotic factors (FLIP, BCL-2, Bcl-xl, IAP family members) [10], active DNA repair capacity [11], up-regulation of cell pumps such as the multidrug resistance transporter (MDR1) [4] and increased metabolic activity through ALDH1 [12]. By stabilizing the cysteine transporter subunit xCT and, thereby, regulating the intracellular levels of reduced glutathione (GSH), a primary intracellular antioxidant, CSCs are also able to protect themselves from ROS-inducing anticancer drugs [13]. Lastly, CSCs can be difficult to reach because they reside in a permissive environment that protects them from diverse genotoxic insults [14, 15].

In addition, to sustain CSCs functional traits [16, 17], the tumor microenvironment is also involved in the CSC generation through induction of “stemness” features into differentiated tumor cells [18, 19]. Along this line, HGF-producing myofibroblasts are able to provide a CSC phenotype to non-CSC, by reactivating the Wnt signaling pathway. These dedifferentiated cancer cells acquire the expression of stem cell-associated genes but also gain tumorigenic potential [20]. The unexpected plasticity of CSCs enables these cells to change their phenotype and to assume different functions and properties, including a stem cell state. Epithelial cells undergoing the epithelial-to-mesenchymal transition (EMT) lose polarity and cell-to-cell adhesion properties. However, they acquire a mesenchymal-like phenotype associated with increased motility, invasiveness and resistance to apoptosis [21]. CSCs can be also generated by inducting the EMT program, which stimulates the expression of CSCs markers and increases tumorigenic potential [22]. By either down-regulating “stemness”-repressed microRNAs [23, 24] or by inducing expression of Bmi-1 [25], EMT-inducing factors, like cytokines and hypoxia, stimulate the expression of transcription factors associated to self-renewal program.

Recent data show that cytokines secreted by the tumor microenvironment, including HGF, osteopontin and stromal-derived factor 1a, reprogram colorectal CD44v6progenitors in metastatic stem cells by increasing the CD44v6 expression via the Wnt pathway activation. Survival analysis, conducted by using Kaplan-Meier curves, revealed that in patient cohorts, low levels of CD44v6 predict increased probability of disease-free survival. Importantly, the inhibition of phosphatidylinositol 3-kinase (PI3K) that selectively killed CD44v6 expressing CSCs has been shown to be effective in reducing the metastatic process initiated by CSCs, through the expression of CD44v6 [26].

These evidences underline the importance of studying the complex interplay between CSCs and the tumor microenvironment, which may lead to the identification of novel drug candidates.

It has been extensively demonstrated that the immune system plays a relevant role in the control of tumor growth; in fact, lost of immunity is associated with cancer risk, and on the other hand efficient systemic immune responses can lead to tumor killing [27, 28]. The interplay between tumor development and the immune system has been re-defined by a step-wise process that includes 3 different phases (3E), early elimination, equilibrium and escape [29]. The concept that the immune infiltrate at tumor site can have prognostic significance has been initially proposed by Mihm et al. [30] for melanoma; then it was extended to other neoplastic tissues and, more recently, it was quantitatively and molecularly defined leading to the development of the immunoscore as an efficient prognostic tool for solid tumors [31].

Despite the fact that in the last two decades a variety of molecular and regulatory features of tumor immunology have been extensively dissected, effective therapeutic vaccines for solid tumors have not yet been convincingly obtained; an overall 10–20 % of clinical responses have been observed. A possible explanation for these disappointing clinical results may lie in the failure to elicit effective and persistent immune responses by tumor vaccine in cancer patients. On the other hand, many factors can work in concert to inhibit anti-tumor immunity, including the release by tumor cells of suppressive cytokines/factors, the induction of regulatory T lymphocytes (Tregs) and/or myeloid derived suppressor cells (MDSCs) [32–34].

Moreover, the modulation by the complex interactions of co-stimulatory or negative regulatory molecules, defined as immune checkpoint molecules, on antigen presenting (APC)/tumor cells and on effector immune cells has been shown to play a key role in the regulation of anti-cancer immune responses [35]. The clinical development of immune-checkpoint blockade agents showed durable clinical responses and increase of survival for patients with solid tumors with different histological origins [36]. These evidences indicate that immunotherapy represents a promising treatment for cancer patients as it can induce efficient anti-tumor immune responses in these patients. Notably, the effectiveness of immunotherapy could be increased by targeting CSCs that represent the component of the tumor responsible of resistance to standard therapy, such as chemotherapy and radiotherapy, and to immunotherapy as well [11, 37–39].

The characterization of the immunological profile of CSCs and of the relationship between CSCs and anti-tumor immunity, thus, represent a relevant issue to design novel and more effective immunotherapy interventions for cancer patients.

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