Aging-induced immune microenvironment remodeling fosters melanoma in male mice via γδ17-Neutrophil-CD8 axis
Runping Duan, Loujing Jiang, Tianfu Wang, Zhaohuai Li, Xiaoyang Yu, Yuehan Gao, Renbing Jia, Xianqun Fan, Wenru Su
Abstract
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. Aging is a risk factor of cancer, but how an aged immune system transforms the tumor microenvironment (TME) is unclear. By leveraging scRNA-seq analysis in a mouse model of metastatic melanoma, here the authors show that a γδ17-dependent increase in neutrophils inhibits the proliferation and stemness of CD8+ T cells, thereby promoting tumor metastasis.