Bodogai Monica, Park Bongsoo, Braikia Fatima-Zohra, Naqing Fnu, Kumaraswami Konda, Chen Chen, Ragonnaud Emeline, Stack Sharon, Ormanns Steffen, Günther Michael, Ishikawa-Ankerhold Hellen, De Supriyo, Ferrucci Luigi, Sen Ranjan, Duren Zhana, Beerman Isabel, Biragyn Arya
Immunoregulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD, USA.
Epigenetics and Stem Cell Aging Unit, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
Nat Aging. 2025 Oct;5(10):2055-2069. doi: 10.1038/s43587-025-00966-3. Epub 2025 Sep 25.
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.
传统上，与年龄相关的癌症发病率上升被归因于耗竭和功能失调的CD8⁺T细胞抗肿瘤免疫力受损。在此，我们提出一种替代机制：在衰老过程中，癌症也会在功能完全正常的CD8⁺T细胞的帮助下进展。这些在转录和表观遗传上不同的细胞（称为双阳性CD8 T细胞（DP8））在其表面表达CD39、CD73、CD101和CXCR6，并在小鼠健康衰老过程中积累，这需要B细胞呈递同源抗原。在老年小鼠中，进展期肿瘤通过CXCL16-CXCR6轴招募DP8细胞，以ADP/腺苷依赖的方式抑制抗肿瘤CD4 T细胞，靶向DP8细胞功能或招募可以逆转老年小鼠的肿瘤生长。DP8细胞的这种促肿瘤机制似乎在老年人中也存在，因为我们在各种肿瘤中检测到了类似DP8的细胞，包括晚期乳腺癌。我们建议，在为老年人量身定制的治疗方法的开发中，应考虑CD8 T细胞的这种促肿瘤作用。
