Huff et al. review CD8+ T cell senescence, which is hallmarked by loss of CD28 expression. They discuss how senescence is induced, characteristics and functions of senescent T cells, and how senescence compares to other forms of T cell dysfunction (anergy, exhaustion, and tolerance). Senescent T cells can play different roles depending on their context, but in cancer they are typically immunosuppressive and associated with poor prognosis and poor response to checkpoint blockade. Targeting senescent T cells for immunotherapy may involve removing, reprogramming, or replacing them, or restoring the thymic environment.
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. Naive 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.