年龄相关的肿瘤特异性T细胞收缩损害抗肿瘤免疫

Age-Associated Contraction of Tumor-Specific T Cells Impairs Antitumor Immunity

Cancer Immunology Research

影响因子:8.2

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

DOI: 10.1158/2326-6066.CIR-24-0463

摘要

随着年龄增长，适应性免疫系统逐步衰退，伴随癌症发病率的急剧上升。本研究旨在探究老年患者抗肿瘤免疫缺陷是否促进肿瘤进展和/或驱动免疫治疗的耐药。我们发现，多个同源癌症在老年小鼠中的生长速度明显快于年轻小鼠，主要由CD8+ T细胞功能失调驱动。通过系统性分析肿瘤内免疫细胞谱系，确认肿瘤抗原特异性CD8+ T细胞的丧失是加速肿瘤生长和免疫治疗耐药的主要特征。当从年轻小鼠中获取的抗原特异性T细胞被输注到老年小鼠中，肿瘤生长被延迟，老年动物对PD-1阻断治疗变得敏感。这些研究揭示了年龄相关的CD8+ T细胞功能障碍可能促使老年患者肿瘤形成的机制，并对老年动物作为癌症与衰老的前临床模型具有重要意义。

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.