Exhaustion of T lymphocytes in the tumor microenvironment: Significance and effective mechanisms.

T lymphocytes play crucial roles in adaptive immune responses to tumors. However, due to different tolerance mechanisms and inhibitory effects of the tumor microenvironment (TME) on T cells, responses to tumors are insufficient. In fact, cellular and molecular suppressive mechanisms repress T cell responses in the TME, resulting in senescent, anergic and exhausted lymphocytes. Exhaustion is a poor responsive status of T cells, with up-regulated expression of inhibitory receptors, decreased production of effective cytokines, and reduced cytotoxic activity. Low immunogenicity of tumor antigens and inadequate presentation of tumor-specific antigens results in inappropriate activation of naive T lymphocytes against tumor antigens. Moreover, when effector cytotoxic T cells enter TME, they encounter a complicated network of cells and cytokines that suppress their effectiveness and turn them into exhausted T cells. Thus, the mechanism of T cell exhaustion in cancer is different from that in chronic infections. In this review we will discuss the main components such as inhibitory receptors, inflammatory cells, stromal cells, cytokine milieu as well as environmental and metabolic conditions in TME which play role in development of exhaustion. Furthermore, recent therapeutic methods available to overcome exhaustion will be discussed.