PD-L1 Restrains the PD-1hiNrp1loTGFβ+Treg to block IL6+Neutrophil tumor infiltration to Suppress Inflammation-driven Colorectal Cancer

Abstract

SummaryPD-L1 functions as a suppressor of T cell activation and colonic inflammation. The consequence of and mechanism underlying these opposite functions of PD-L1 in colorectal cancer remains unknown. We report that globalCd274deletion promotes inflammation-driven colorectal tumorigenesis. 16S rRNA and shotgun metagenomic sequencing revealed that loss of host PD-L1 leads to expansion of gutLigilactobacillus murinusand activation of the AhR pathway in tumor-bearing mice. scRNA-seq analysis revealed that PD-L1 regulates PD-189Nrp11215Treg, IL6+neutrophils, and B cells in colorectal tumor. Treg expresses high level of TGFβ to recruit IL6+neutrophils. IL6 inhibits activation of B and T cells. IL6 blockade or B cell activation via CD40 agonist increases CTL activation and suppresses colon tumor growth in vivo. Our findings determine that PD-L1 functions as a tumor suppressor in the context of inflammation-driven colorectal cancer and the PD-L1/L. murius/PD-189Nrp11215TGFβ+Treg/IL6+neutrophils pathway controls host cancer immunosurveillance and colorectal tumorigenesis.Key pointsGlobal deletion ofCd274promotes inflammation-driven colorectal tumorigenesis.Loss of PD-L1 increases gutL. murinusand activates AhR pathway in colorectal tumor.PD-1hiTGFβ+Nrp1loTreg recruits IL6+neutrophils to inhibit B and T cell function in colorectal tumor.L. murinusand tryptophan metabolites connect PD-L1 and colorectal tumor immunosurveillance.Graphic summary