Single-Cell Dissection of Concurrent Chemoradiotherapy-Induced Immunosenescence in Cervical Cancer

Abstract

Immunosenescence could attenuate effective anti-tumor immune response, but it's role in the tumor microenvironment following concurrent chemoradiotherapy (CCRT) in cervical cancer (CC) remains largely unknown. We aimed to investigate CCRT induced immunosenescence and its clinical implications in CC at single-cell resolution. A total of 11326 cells from single-cell RNA sequencing data derived from five post-CCRT CC tumor samples were analyzed by bioinformatics for immunosenescence. Functional enrichment analysis including Gene Ontology (GO) and Gene Set Variation analysis was performed to identify and assess the molecular heterogeneity of cell subclusters. Kaplan-Meier survival analysis was performed in the bulk RNA-sequencing data included 253 patients with CC obtained from the The Cancer Genome Atlas. We identified senescent and non-senescent cell clusters in tumor-associated macrophages (TAMs), CD8+ T cells and NK cells after CCRT based on the senescence-related genes expression. GO analysis showed that antigen processing and presentation pathways were enriched in the non-senescent TAMs, while the response to hypoxia and oxidative stress were enriched in the senescent TAMs, which repressed the anti-tumor immunity. We further found that the abundance of senescent TAMs was associated with shorter overall survival (OS) of patients with CC (P<0.001). Moreover, compared to senescent CD8+ T, non-senescent CD8+ T exhibited higher cytotoxicity and exhausted signature scores, and increased enrichment of T cell proliferation, differentiation and activation pathways. In addition, the high proportion of non-senescent NK cell was also associated with better OS of CC patients (P = 0.008). We revealed the potential immune suppressive characteristics of CCRT induced senescent immune cells at single-cell resolution, which provides promising therapeutic targets for CC patients.