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

Abstract

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.

Immune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment

“…CD57 positive T cells can secrete cytokines when stimulated by their cognate peptides however they do not proliferate when stimulated ( 25 ). Tumor resident senescent T cells have also been shown to down regulate the co-stimulatory molecules CD27 and CD28 contributing to immune dysfunction, causing changes in APC phenotype such as a down regulation of CD80 and CD86 reducing their ability to stimulate T cells further exacerbating the local immune dysfunction ( 26 ). When compared to healthy donors GBM patients have a lower number of circulating CD3 + T cells in their peripheral blood mononuclear cells (PBMCs) further indicating a disease related immune dysfunction ( 27 ).…”

Phenotype molding of T cells in colorectal cancer by single‐cell analysis

“…b ). CD28 family of co‐stimulatory molecules also comprise ICOS, CTLA‐4 and PD‐1; CD28 (activating) and CTLA‐4 (inhibitory) are highly homologous and compete for the same ligands to regulate immune response by exerting opposite effects . Interestingly, CD8+ CD28+ T cells also express high levels of CTLA4 and ICOS, and are positive for activation markers CD38, CCR7, and HLA‐DR, indicative of the exhausted status.…”

“…The decrease in the expression of CD28 is a hallmark of senescent T cells . CD8+ CD28− T cells were reported to exhibit controversial functions as immunosuppressive and cytotoxic agents in anticancer immunity .…”

Immunosenescence: a key player in cancer development

“…T cell senescence is irreversible, as opposed to their anergy and exhaustion, both of which are considered reversible [31,[38][39][40]. Age-related immune biomarkers, such as the downregulation of the costimulatory molecule CD28 of senescent T cells, have also been employed in several senescence studies [41], which do not express costimulatory molecules such as CD27 and CD28 but express the killer cell lectin-like receptor subfamily G (KLRG-1) and CD57. Therefore, the T cell phenotype of CD27 − CD28 − CD57 + KLRG-1 + is also an indicator of immunosenescence.…”