Senescent Tumor CD8(+) T Cells: Mechanisms of Induction and Challenges to Immunotherapy

SIMPLE SUMMARY: Immunotherapies harness the hosts’ immune system to combat cancer and are currently used to treat many tumor types. Immunotherapies mainly target T cells, the major immune population responsible for tumor-cell killing. One of the reasons that T cells may not respond to immunotherapeutic treatment is that they are in a dysfunctional state termed senescence. This review seeks to describe the molecular mechanisms that characterize and induce T cell senescence within the context of the tumor microenvironment and how this might affect treatment responses. ABSTRACT: The inability of tumor-infiltrating T lymphocytes to eradicate tumor cells within the tumor microenvironment (TME) is a major obstacle to successful immunotherapeutic treatments. Understanding the immunosuppressive mechanisms within the TME is paramount to overcoming these obstacles. T cell senescence is a critical dysfunctional state present in the TME that differs from T cell exhaustion currently targeted by many immunotherapies. This review focuses on the physiological, molecular, metabolic and cellular processes that drive CD8(+) T cell senescence. Evidence showing that senescent T cells hinder immunotherapies is discussed, as are therapeutic options to reverse T cell senescence.