B cells induce the age-related accumulation of CD39+CD73+ CD8+ T cells 2305676

Abstract

Abstract Introduction Even in “healthy” aging, adaptive immune cells become dysregulated, increasing age-associated B cells and exhausted and senescent T cells in the circulation. Although the clinical consequence of this dysregulation remains poorly understood, we previously reported that aged B cells, through the induction of cytolytic CD8+ T cells, can be responsible for the surprising suppression of orthotopic B16-F10 melanoma in aged C57BL/6 mice. Despite this, it remains unclear why this pathway fails to prevent the age-associated increase in other cancers. Methods We performed comprehensive flocytometric analysis combined with scRNA-seq and ATC-seq of adaptive immune cells in young (8-20 weeks old) and aged (17-20 months old) mice. Results While the age-related cancer increase can be explained by exhaustion or senescence of T cells, we do not detect significant accumulation of these cells in aged mice. Instead, we find that aged mice markedly increase a previously unknown subset of CD8+ cells expressing CXCR6 and adenosine-generating CD39 and CD73. These cells (termed DP8), which are also induced by aged B cells, appear to play the key role in the increase of cancer in aged mice. Unlike cancers that regress, cancers that progress in aged mice recruit DP8 cells through the production of CXCL16, which then suppress antitumor CD4+ T cells by generating immunoregulatory adenosine using their ectonucleotidases CD39 and CD73. Conclusion Our results underscore the importance of aged B cells in cancer. By targeting B cells, aging elicits both cancer-promoting and cancer-blocking CD8+ T cells. Funding Source This work was supported by the Intramural Research Program, National Institute on Aging Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)