与年龄相关的肿瘤特异性T细胞的收缩会损害抗肿瘤免疫力
Age-Associated Contraction of Tumor-Specific T Cells Impairs Antitumor Immunity
影响因子:8.20000
分区:医学1区 Top / 免疫学2区 肿瘤学2区
发表日期:2024 Nov 04
作者:
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
摘要
随着年龄的增长，适应性免疫系统的逐步下降与癌症发生率急剧增加相吻合。在这项研究中，我们着手了解抗肿瘤免疫缺陷是否会促进肿瘤进展和/或抗免疫疗法的抗性。我们发现，由CD8+ T细胞反应功能障碍驱动的年龄相对于年轻小鼠，多种同基因癌在老年人与年轻小鼠相比生长更快。通过系统地映射肿瘤中的免疫细胞谱，我们确定了肿瘤抗原特异性CD8+ T细胞的丧失，是衰老小鼠中肿瘤生长的主要特征，并驱动了对免疫疗法的耐药性。当将来自年轻小鼠的抗原特异性T细胞施用到老年小鼠中时，肿瘤生长会延迟，而老年动物对PD-1封锁敏感。这些研究揭示了与年龄相关的CD8+ T细胞功能障碍如何在老年患者中许可肿瘤发生，并且对将老年小鼠用作老龄化和癌症的临床前模型具有重要意义。
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.