N-6-Methyladenosine (m(6)A) 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 m(6)A-dependent. m(6)A "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.
基金：
Shanghai Fourth People's Hospital [sykyqd04401, sykyqd05101]; Science and Technology Commission of Shanghai Hongkou District [hongwei2202-19]; Medical engineering of Shanghai Jiao Tong University [YG2022QN115]
第一作者机构：[1]Tongji Univ, Shanghai Peoples Hosp 4, Sch Med, Dept Gastrointestinal Surg, Shanghai, Peoples R China
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推荐引用方式(GB/T 7714)：
Liu Qi-Zhi,Zhang Nan,Chen Jun-Yi,et al.WTAP-induced N6-methyladenosine of PD-L1 blocked T-cell-mediated antitumor activity under hypoxia in colorectal cancer[J].CANCER SCIENCE.2024,115(6):1749-1762.doi:10.1111/cas.16136.
APA：
Liu, Qi-Zhi,Zhang, Nan,Chen, Jun-Yi,Zhou, Min-Jun,Zhou, De-Hua...&Tu, Xiao-Huang.(2024).WTAP-induced N6-methyladenosine of PD-L1 blocked T-cell-mediated antitumor activity under hypoxia in colorectal cancer.CANCER SCIENCE,115,(6)
MLA：
Liu, Qi-Zhi,et al."WTAP-induced N6-methyladenosine of PD-L1 blocked T-cell-mediated antitumor activity under hypoxia in colorectal cancer".CANCER SCIENCE 115..6(2024):1749-1762
医学