WTAP‐induced N6‐methyladenosine of PD‐L1 blocked T‐cell‐mediated antitumor activity under hypoxia in colorectal cancer

Abstract

AbstractN6‐Methyladenosine (m6A) is a important process regulating gene expression post‐transcriptionally. Programmed death ligand 1 (PD‐L1) is a major immune inhibitive checkpoint that facilitates immune evasion and is expressed in tumor cells. In this research we discovered that Wilms' tumor 1‐associated protein (WTAP) degradation caused by ubiquitin‐mediated cleavage in cancer cells (colorectal cancer, CRC) under hypoxia was inhibited by Pumilio homolog 1 (PUM1) directly bound to WTAP. WTAP enhanced PD‐L1 expression in a way that was m6A‐dependent. m6A “reader,” Insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2) identified methylated PD‐L1 transcripts and subsequently fixed its mRNA. Additionally, we found that T‐cell proliferation and its cancer cell‐killing effects were prevented by overexpression of WTAP in vitro and in vivo. Overexpression prevented T cells from proliferating and killing CRC by maintaining the expression of PD‐L1. Further evidence supporting the WTAP–PD‐L1 regulatory axis was found in human CRC and organoid tissues. Tumors with high WTAP levels appeared more responsive to anti‐PD1 immunotherapy, when analyzing samples from patients undergoing treatment. Overall, our findings demonstrated a novel PD‐L1 regulatory mechanism by WTAP‐induced mRNA epigenetic regulation and the possible application of targeting WTAP as immunotherapy for tumor hypoxia.