The Evolving Role of CD8(+)CD28(−) Immunosenescent T Cells in Cancer Immunology

Functional, tumor-specific CD8(+) cytotoxic T lymphocytes drive the adaptive immune response to cancer. Thus, induction of their activity is the ultimate aim of all immunotherapies. Success of anti-tumor immunotherapy is precluded by marked immunosuppression in the tumor microenvironment (TME) leading to CD8(+) effector T cell dysfunction. Among the many facets of CD8(+) T cell dysfunction that have been recognized—tolerance, anergy, exhaustion, and senescence—CD8(+) T cell senescence is incompletely understood. Naïve CD8(+) T cells require three essential signals for activation, differentiation, and survival through T-cell receptor, costimulatory receptors, and cytokine receptors. Downregulation of costimulatory molecule CD28 is a hallmark of senescent T cells and increased CD8(+)CD28(−) senescent populations with heterogeneous roles have been observed in multiple solid and hematogenous tumors. T cell senescence can be induced by several factors including aging, telomere damage, tumor-associated stress, and regulatory T (Treg) cells. Tumor-induced T cell senescence is yet another mechanism that enables tumor cell resistance to immunotherapy. In this paper, we provide a comprehensive overview of CD8(+)CD28(−) senescent T cell population, their origin, their function in immunology and pathologic conditions, including TME and their implication for immunotherapy. Further characterization and investigation into this subset of CD8(+) T cells could improve the efficacy of future anti-tumor immunotherapy.