Targeting CAFs-derived PCSK6 inhibits redistribution of PD-L1 and restores response of CD8+T cells against colorectal cancer

Abstract Carcinoma-associated fibroblasts (CAFs) are core components of the tumor microenvironment, which contribute to tumor initiation and progression through mediating immune suppression. In this study, eight activated CAF subpopulations were identified by single-cell sequencing (scRNA-seq). A specific subtype of CAFs, characterized by PCSK6 expression, strengthened PD-L1 membrane distribution, which contributed to the cytotoxic CD8 + T cells exhaustion, subsequently promoting the progression of colorectal cancer (CRC). PCSK6 interacting with ACVR1B on CRC cell surface, promoting the acetylation modification of PD-L1 via acetyltransferase p300, followed by strengthened PD-L1 membrane distribution. Loss of PCSK6/ACVR1B signaling in tumor stroma enhanced the intratumoral infiltration and activation of CD8 + T cells, alleviated growth of CRC and conferred survival advantage in tumor-bearing mice. Moreover, the membrane level of PD-L1 was mediated by the membrane transport complex Rab8/EHBP1L1. Our finding suggested PCSK6/ACVR1B-p300-Rab8/EHBP1L1-PD-L1 signaling axis is significantly activated by CAFs-derived PCSK6, which may offer mechanism interpretation for CAFs mediated CRC immune escape and suggest potential mechanism-based therapeutic strategies for ACVR1B antagonist.