Age-Associated Contraction of Tumor-Specific T Cells Impairs Antitumor Immunity
Peter Georgiev, SeongJun Han, Amy Y. Huang, Thao H. Nguyen, Jefte M. Drijvers, Hannah Creasey, Joseph A. Pereira, Cong-Hui Yao, Joon Seok Park, Thomas S. Conway, Megan E. Fung, Dan Liang, Michael Peluso, Shakchhi Joshi, Jared H. Rowe, Brian C. Miller, Gordon J. Freeman, Arlene H. Sharpe, Marcia C. Haigis, Alison E. Ringel
Abstract
Progressive decline of the adaptive immune system with increasing age coincides with a sharp increase in cancer incidence. In this study, we set out to understand whether deficits in antitumor immunity with advanced age promote tumor progression and/or drive resistance to immunotherapy. We found that multiple syngeneic cancers grew more rapidly in aged versus young adult mice, driven by dysfunctional CD8+ T-cell responses. By systematically mapping immune cell profiles within tumors, we identified loss of tumor antigen-specific CD8+ T cells as a primary feature accelerating the growth of tumors in aged mice and driving resistance to immunotherapy. When antigen-specific T cells from young adult mice were administered to aged mice, tumor outgrowth was delayed and the aged animals became sensitive to PD-1 blockade. These studies reveal how age-associated CD8+ T-cell dysfunction may license tumorigenesis in elderly patients and have important implications for the use of aged mice as preclinical models of aging and cancer.