Aging Induces CD8+ T Cells to Support Cancer Progression

The role of CD8+ T cell exhaustion in cancer in aging remains poorly understood. Although it is assumed that the age-related accumulation of exhausted, and thus dysfunctional, CD8+ T cells would increase tumor growth, in this study we provide an alternative paradigm: tumors in aged, but not young hosts, progress by actively using CD8+ T cells. These CD8+ T-cells are transcriptionally and epigenetically distinct and non-exhausted expressing the cell surface immunophenotype CXCR6+ CD39+ CD73+ CD101+ CD8+ (termed DP8). They accumulate in healthy aging, and at least in part, after induction with B cells presenting cognate antigens. Tumors that progress in aged mice recruit DP8 cells via the CXCL16/CXCR6 axis to suppress anti-tumor CD4+ T cells in an ADP/adenosine-dependent manner. This tumor-enhancing mechanism of DP8 cells appears to be active in older humans, as we detected DP8-like cells in various tumors, including late-onset breast cancer. We propose this novel tumor-promoting role of CD8+ T cells should be considered in the development of therapeutics tailored for the elderly as, targeting DP8 cell function or recruitment can reverse tumor growth in aged mice. ATAC sequencig were performed to compare the epigenome between AT3 and B16 tumor samples