Dynamic cross-talk between tumor and immune cells in orchestrating the immunosuppressive network at the tumor microenvironment

Abstract

Accumulating evidence indicates that a dynamic cross-talk between tumors and the immune system can regulate tumor growth and metastasis. Increased understanding of the biochemical nature of tumor antigens and the molecular mechanisms responsible for innate and adaptive immune cell activation has revolutionized the fields of tumor immunology and immunotherapy. Both the protective effects of the immune system against tumor cells (immunosurveillance) and the evasion of tumor cells from immune attack (tumor-immune escape) have led to the concept of cancer immunoediting, a proposal which infers that a bidirectional interaction between tumor and inflammatory/regulatory cells is ultimately responsible for orchestrating the immunosuppressive network at the tumor site. In this context, a major challenge is the potentiation or redirection of tumor antigen-specific immune responses. The success in reaching this goal is highly dependent on an improved understanding of the interactions and mechanisms operating during the different phases of the cancer immunoediting process. In this review, we discuss the multiple defense and counterattack strategies that tumors have devised in order to evade immune attack and to thwart the effectiveness of several immunotherapeutic approaches.

Fig. 1

Immunosuppressive strategies used by tumors to evade immune responses. Tumors employ a plethora of immunosuppressive mechanisms, which may act in concert to counteract effective immune responses. These include tumor-induced impairment of the antigen presentation machinery, activation of negative costimulatory signals in the tumor microenvironment (CTLA-4/B7, PD-1/PD-L1, Fas/ FasL), elaboration of immunosuppressive factors (IL-10, TGF-β, galectin-1, gangliosides, PGE ₂), and overexpression of indoleamine 2,3 dioxygenase (IDO). In addition, different regulatory cell populations contribute to this immunosuppressive network including CD4 ⁺ CD25 ⁺ regulatory T-cells (Tregs) and inducible T regulatory (Tr1) cells which negatively impact on the fate of effector T cells. Abbreviations: Gal-1 galectin-1, PGE ₂ prostaglandin-E₂, TGF-β transforming growth factor-β, MHC-I major histocompatibility complex, TAP transporter-associated protein