Dual regulation of CXCR6+CD8+ T cells drives immune exhaustion in the progression of prostate cancer [PB-Cre; Pten knockout and WT]

To disclose the mechanisms underlying immune exclusion, we performed single-cell RNA sequencing (scRNA-seq) of tumor-infiltrating immune cells from patients with PCa and identified a previously unappreciated subset of CXCR6+CD8+ cytotoxic T lymphocytes (CXCR6+ CTLs).

Notably, the abundance of these cells was inversely correlated with Gleason Score (GS), indicating progressive depletion in advanced stages of PCa. Mechanistically, this depletion is modulated by dual converging pathways. On the one hand, reduced infiltration of M1-like macrophages in higher-grade tumors leads to diminished production of CXCL16, thereby impairing the recruitment of CXCR6⁺ CTLs; On the other hand, IL-10 derived from the tumor microenvironment, partly from M2-like macrophages, downregulates CXCR6 expression via the IL10–FOXO1–KLF2 transcriptional axis.