The immune system recognizes cancerous cells by screening the tumor antigen during malignant progression. By producing cytokines, the cells of the immune system have the ability to arrest division and migration of cancer cells. Cancer cells commonly change the cytokine profile so that the innate and adaptive immune cells are differentiated in the tumor microenvironment. Cytotoxic T lymphocytes (CTL), which are exposed to the microenvironment in tumor tissues and peripheral blood, lose their antitumor activity and express inhibitor marker on their surface. In fact, these lymphocytes are transformed to exhausted T cells with different features in phenotype and performance.
Investigations have shown that the exhausted T cells give rise to resistance against chemotherapy and develop angiogenesis by interleukin (IL)-8 and IL-6 production.The limitations in specific antigen diagnosis and T cell activation have led to the limitation of using novel immunotherapy techniques, such as chimeric antigen receptor (CAR) and T cell receptor (TCR) transgenic T cells. Recently, some immune checkpoint inhibitors, such as ipilimumab, act against inhibitor markers and have replaced chemotherapy and radiotherapy in melanoma and some sorts of leukemia. Although these antibodies seem to be effective drugs to activate exhausted T cells, they create systemic complications, such as diarrhea in the gastrointestinal tract, rash, pancreatitis, and autoimmune diseases.
