PD-L1 restrains PD-1+Nrp1lo Treg cells to suppress inflammation-driven colorectal tumorigenesis

T cells function not only as an essential component of host cancer immunosurveillance but also as a regulator of colonic inflammation, a process that promotes colorectal cancer. Programmed death-ligand 1 (PD-L1) is a T cell-negative regulator, but its role in regulation of T cell functions in the context of colorectal cancer is unknown. We report that global deletion of Cd274 results in increased colonic inflammation, PD-1+ T cells, and inflammation-driven colorectal tumorigenesis in mice. Single-cell RNA sequencing (scRNA-seq) analysis revealed that PD-L1 suppresses subpopulations of programmed cell death protein 1 (PD-1)+Nrp1lo regulatory T (Treg) cells and interleukin (IL) 6+ neutrophils in colorectal tumor. Treg cells produce transforming growth factor (TGF) β to recruit IL6+ neutrophils. Neutrophils produce IL6 to inhibit activation of tumor-specific cytotoxic T lymphocytes (CTLs) and primary CTLs. Accordingly, IL6 blockade immunotherapy increases CTL activation and suppresses colon tumor growth in vivo. Our findings determine that PD-L1 restrains PD-1+Nrp1loTGFβ+ Treg cells to suppress IL6+ neutrophil tumor recruitment to sustain CTL activation to control inflammation-driven colorectal tumorigenesis.