Implications of Senescent T Cells for Cancer Immunotherapy

Simple Summary Senescent T cells are defective in proliferation and effector functions, and they accumulate owing to aging, chronic viral infections, and autoimmune diseases. Several DNA-damaging chemotherapeutic agents, such as melphalan and doxorubicin, induce senescence in cancer cells. However, it is unclear whether these agents induce senescence in T cells. We evaluated whether sublethal doses of melphalan and doxorubicin induce cellular senescence in human peripheral blood mononuclear cell-derived T cells from healthy donors. Our results demonstrate that therapy-induced cellular senescence is also induced in T cells and that PD-1 may be a biomarker for therapy-induced senescent T cells. In this review, we discuss the characteristics of senescent T-cells, including therapy-induced senescent T-cells. In addition, we investigate whether therapy-induced cellular senescence has positive and/or negative effects on T cells.Abstract T-cell senescence is thought to result from the age-related loss of the ability to mount effective responses to pathogens and tumor cells. In addition to aging, T-cell senescence is caused by repeated antigenic stimulation and chronic inflammation. Moreover, we demonstrated that T-cell senescence was induced by treatment with DNA-damaging chemotherapeutic agents. The characteristics of therapy-induced senescent T (TIS-T) cells and general senescent T cells are largely similar. Senescent T cells demonstrate an increase in the senescence-associated beta-galactosidase-positive population, cell cycle arrest, secretion of senescence-associated secretory phenotypic factors, and metabolic reprogramming. Furthermore, senescent T cells downregulate the expression of the co-stimulatory molecules CD27 and CD28 and upregulate natural killer cell-related molecules. Moreover, TIS-T cells showed increased PD-1 expression. However, the loss of proliferative capacity and decreased expression of co-stimulatory molecules associated with T-cell senescence cause a decrease in T-cell immunocompetence. In this review, we discuss the characteristics of senescent T-cells, including therapy-induced senescent T cells.