Abstract
Simple SummaryImmunotherapies 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.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.
Highlights
Harnessing the immune system to treat solid and hematological malignancies has ushered a novel therapeutic era
A major obstacle is the inability to effectively target Tc cells. This can occur through Tc intrinsic or acquired resistance helped by dysfunctional states present within the immunosuppressive networks [8] of the tumor microenvironment (TME): exhaustion and senescence
This review focuses on senescence in the CD8+ T cell compartment
Summary
Harnessing the immune system to treat solid and hematological malignancies has ushered a novel therapeutic era. A major obstacle is the inability to effectively target Tc cells This can occur through Tc intrinsic or acquired resistance helped by dysfunctional states present within the immunosuppressive networks [8] of the TME: exhaustion and senescence. While T cell exhaustion has been extensively studied and targeted, T cell senescence, especially within the context of anti-tumor immunity, is an emerging concept in the field of T cell dysfunction. This review focuses on senescence in the CD8+ T cell compartment It aims to explore the different mechanisms that induce senescence in the context of TME, ways in which T cell senescence affects responses to immunotherapies and how T cell senescence can be therapeutically reversed
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