Duan Runping, Jiang Loujing, Wang Tianfu, Li Zhaohuai, Yu Xiaoyang, Gao Yuehan, Jia Renbing, Fan Xianqun, Su Wenru
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China.
Guangzhou University of Chinese Medicine, Guangzhou, 510060, China.
Nat Commun. 2024 Dec 30;15(1):10860. doi: 10.1038/s41467-024-55164-3.
Aging is associated with increased tumor metastasis and poor prognosis. However, how an aging immune system contributes to the process is unclear. Here, single-cell RNA sequencing reveals that in male mice, aging shifts the lung immune microenvironment towards a premetastatic niche, characterized by an increased proportion of IL-17-expressing γδT (γδ17) and neutrophils. Mechanistically, age-dependent downregulation of the immune trafficking receptor S1pr1 drives the expansion of γδ17. Compared to young mice, expanded γδ17 recruit tumor-promoting neutrophils with lower expression levels of CD62L and higher levels of C-kit and CXCR4. These neutrophils suppress the stemness and tumor-killing functions of CD8+ T cells in aged male mice. Accordingly, antibody-mediated depletion of γδT or neutrophils reduces tumor metastatic foci in aged animals, and the administration of the senolytic agent procyanidin C1 reverses the observed immune-mediated, tumor-promoting effects of aging. Thus, we uncover a γδ17-Neutrophil-CD8 axis that promotes aging-driven tumor metastasis in male mice and provides potential insights for managing metastatic tumors.
衰老与肿瘤转移增加和预后不良相关。然而，衰老的免疫系统如何促成这一过程尚不清楚。在这里，单细胞RNA测序显示，在雄性小鼠中，衰老使肺免疫微环境向转移前生态位转变，其特征是表达白细胞介素-17的γδT细胞（γδ17）和中性粒细胞的比例增加。从机制上讲，免疫运输受体S1pr1的年龄依赖性下调驱动了γδ17的扩增。与年轻小鼠相比，扩增的γδ17招募了促进肿瘤的中性粒细胞，这些中性粒细胞的CD62L表达水平较低，C-kit和CXCR4水平较高。这些中性粒细胞抑制了老年雄性小鼠中CD8 + T细胞的干性和肿瘤杀伤功能。因此，抗体介导的γδT细胞或中性粒细胞耗竭减少了老年动物的肿瘤转移灶，而衰老细胞溶解剂原花青素C1的给药逆转了观察到的衰老的免疫介导的、促进肿瘤的作用。因此，我们揭示了一个γδ17-中性粒细胞-CD8轴，该轴促进雄性小鼠中衰老驱动的肿瘤转移，并为治疗转移性肿瘤提供了潜在的见解。
