A distinct population of CD8⁺ T cells expressing CD39 and CD73 accumulates with age and supports cancer progression.

Abstract

Age-related increases in cancer have traditionally been attributed to compromised antitumor immunity of exhausted and dysfunctional CD8⁺ T cells. Here we provide an alternative mechanism: in aging, cancer also progresses with the help of fully functional CD8⁺ T cells. These transcriptionally and epigenetically distinct cells (termed double-positive CD8⁺ T cells (DP8)) express CD39, CD73, CD101 and CXCR6 on their surface and accumulate during healthy aging in mice, requiring B cells presenting cognate antigens. In aged mice, progressing tumors recruit DP8 cells via the CXCL16-CXCR6 axis to suppress antitumor CD4⁺ T cells in an ADP/adenosine-dependent manner, and targeting DP8 cell function or recruitment can reverse tumor growth in aged mice. This tumor-promoting mechanism of DP8 cells appears to be conserved in older humans, as we detected DP8-like cells in various tumors, including late-onset breast cancer. We propose that this tumor-promoting role of CD8⁺ T cells should be considered in the development of therapeutics tailored for older humans.