Tumor Cells

It should be recognized that tumor cells sit at the center of the immune biology of cancer and they are likely to be directly or indirectly involved in orchestrating the nature and characteristics of the environment in which they are growing. Tumor cells can cunningly produce molecules that improve their growth, survival and migration potential and at the same time may suppress unwanted immune-responses. As proposed by others [115], tumors can be characterized by seven hallmarks: self sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis and tissue invasion and metastasis, and avoidance of immune-surveillance. All these processes involve molecules that affect the immune response, like IL-4 and 10 (inducing Th-2 differentiation), IL-6 that suppresses inflammation, TGF-0 that inhibits T cells proliferation and antigen presentation and NK cytotoxicity and activate Treg cells. Obviously, things are not as simple as represented in fabricated experimental models. For instance, we have noted that IL-10 expression at the transcriptional and protein level is a positive predictor of immune responsiveness [116, 117]. This observation parallels pre-clinical experimental models in which the systemic or local effects of IL-10 are against tumor growth [60]. We hypothesized that while IL-10 may hamper immune responsiveness in the steady state biology of naturally growing tumors, they may precondition APC [60] and or NK cells [117] to become powerful immune stimulators and effectors during immune therapy. Although tumor cells may alter immune responses by presenting a mechanical barrier composed of infiltrating stroma [118] that may preventing efficient T cell priming and expansion [119], they may also express factors like the tumor-necrosis factor superfamily member LIGHT that can that induce massive naive T lymphocytes infiltration associated with upregulation of both chemokine production and expression of adhesion molecules [120]. Overall, the direct study of the human tumor microenvironment as a predictor of immune responsiveness has not been sufficiently explored although tools are available for such studies [114]. We observed studying a limited number of melanoma metastases that those likely to respond to immunotherapy consisting of the systemic administration of interleukin-2 display immunological signatures different from those unlikely to respond to therapy even before the treatment is administered [113]. In particular, metastases that respond to therapy are characterized by a chronic inflammatory state that does not appear to be sufficient to induce spontaneous tumor regression but facilitates the activation of an acute inflammatory state under systemic immune stimulation [45]. This notion is also supported by the finding that melanomas with better prognosis display transcriptional signatures suggesting of enhanced immunological activity [121]. Similarly, renal cell carcinomas likely to respond to immunotherapy with systemic interleukin-2 display before treatment high level of expression of carbonic anhydrase IX [122] at the transcriptional and protein level which is, in turn, associated with signatures of immune activation [123].

In summary, we believe that tumor cells are the major orchestrators of immune responsiveness. Melanoma and renal cell carcinomas, which are characterized by enhanced immune responsiveness, display a particular immune environment reflected by tissue-restricted signatures suggesting of enhanced immune activation [124]. The biology of these immune responsive tumors cannot induce spontaneous tumor regression in most cases; however, it fosters micro environmental conditions conducive to the acute inflammatory process necessary for the successful activation of immune effector mechanisms [5] if appropriate stimulation is provided and future clinical studies should investigate systemic and local strategies aimed at the activation of the efferent arm of the immune response within the target organ [31].

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