PD-L1 Restrains the PD-1 hi Nrp1 lo TGFβ ⁺ Treg to block IL6 ⁺ Neutrophil tumor infiltration to Suppress Inflammation-driven Colorectal Cancer

Summary PD-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 global Cd274 deletion promotes inflammation-driven colorectal tumorigenesis. 16S rRNA and shotgun metagenomic sequencing revealed that loss of host PD-L1 leads to expansion of gut Ligilactobacillus murinus and activation of the AhR pathway in tumor-bearing mice. scRNA-seq analysis revealed that PD-L1 regulates PD-1 89 Nrp1 1215 Treg, 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-1 89 Nrp1 1215 TGFβ + Treg/IL6 + neutrophils pathway controls host cancer immunosurveillance and colorectal tumorigenesis. Key points Global deletion of Cd274 promotes inflammation-driven colorectal tumorigenesis. Loss of PD-L1 increases gut L. murinus and activates AhR pathway in colorectal tumor. PD-1 hi TGFβ + Nrp1 lo Treg recruits IL6 + neutrophils to inhibit B and T cell function in colorectal tumor. L. murinus and tryptophan metabolites connect PD-L1 and colorectal tumor immunosurveillance. Graphic summary