Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts.
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts.
Cancer Immunol Res. 2024 Nov 4;12(11):1525-1541. doi: 10.1158/2326-6066.CIR-24-0463.
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.
随着年龄的增长，适应性免疫系统逐渐衰退，同时癌症的发病率也急剧上升。在这项研究中，我们旨在了解衰老导致的抗肿瘤免疫缺陷是否会促进肿瘤的进展和/或导致对免疫疗法的耐药性。我们发现，在衰老的而非年轻的成年小鼠中，多种同种异体癌症的生长速度更快，这是由功能失调的 CD8+T 细胞反应驱动的。通过系统地绘制肿瘤内免疫细胞的图谱，我们发现肿瘤抗原特异性 CD8+T 细胞的缺失是加速衰老小鼠肿瘤生长并导致对免疫治疗耐药的主要特征。当从小鼠中分离出的抗原特异性 T 细胞被给予衰老的小鼠时，肿瘤的生长速度会减慢，并且衰老的动物对 PD-1 阻断变得敏感。这些研究揭示了衰老相关的 CD8+T 细胞功能障碍如何可能导致老年患者的肿瘤发生，并对使用衰老小鼠作为衰老和癌症的临床前模型具有重要意义。
