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.