Abstract
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 Tcell-negative regulator, but its role in regulation of Tcell functions in the context of colorectal cancer is unknown. We report that global deletion of Cd274 results in increased colonic inflammation, PD-1+ Tcells, 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 invivo. 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.
Published Version
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