PD-L1 Restrains the PD-1^hiNrp1^loTGFβ⁺Treg to block IL6⁺Neutrophil tumor infiltration to Suppress Inflammation-driven Colorectal Cancer

Abstract

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-1hiNrp1lo 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-1hiNrp1loTGFβ+ Treg/IL6+ neutrophils pathway controls host cancer immunosurveillance and colorectal tumorigenesis.