Age-Associated Contraction of Tumor-Specific T Cells Impairs Antitumor Immunity
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.
Authors
- Joseph A. Pereira (ORCID: https://orcid.org/0000-0003-2341-8461)
- Amy Y. Huang (ORCID: https://orcid.org/0000-0002-6646-6503)
- Hannah Creasey
- SeongJun Han (ORCID: https://orcid.org/0000-0002-7070-3049)
- Brian C. Miller (ORCID: https://orcid.org/0000-0001-5931-4184)
- Thao H. Nguyen (ORCID: https://orcid.org/0000-0002-2767-0528)
- Arlene H. Sharpe (ORCID: https://orcid.org/0000-0002-9736-2109)
- Shakchhi Joshi (ORCID: https://orcid.org/0000-0002-3120-7659)
- Peter Georgiev (ORCID: https://orcid.org/0000-0002-4613-1255)
- Marcia C. Haigis (ORCID: https://orcid.org/0000-0003-2530-2681)
- Alison E. Ringel (ORCID: https://orcid.org/0000-0002-6451-9376)
- Michael Peluso (ORCID: https://orcid.org/0000-0002-6317-4812)
- Jefte M. Drijvers (ORCID: https://orcid.org/0000-0002-5675-5643)
- Cong-Hui Yao
- Megan E. Fung (ORCID: https://orcid.org/0000-0002-9053-0915)
- Gordon J. Freeman (ORCID: https://orcid.org/0000-0002-7210-5616)
- Thomas S. Conway (ORCID: https://orcid.org/0009-0006-9757-5995)
- Jared H. Rowe (ORCID: https://orcid.org/0000-0002-4223-4433)
- Joon Seok Park (ORCID: https://orcid.org/0000-0003-4001-6886)
- Dan Liang (ORCID: https://orcid.org/0000-0001-7363-4803)
Institutions
- University of North Carolina at Chapel Hill (US)
- Brigham and Women's Hospital (US)
- Boston Biomedical Research Institute (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Dana-Farber Cancer Institute (US)
- Harvard Stem Cell Institute (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Cancer Immunology Research
- Published
- 2024-08-26
- DOI
- https://doi.org/10.1158/2326-6066.cir-24-0463
- Citations
- 16
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 3.85
Funders
- American Cancer Society
- Glenn Foundation for Medical Research
- Fondation pour la Recherche Médicale
- National Institutes of Health
- Ludwig Center at Harvard
- Canadian Institutes of Health Research
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases