Decreased Expression of Programmed Death Ligand-L1 by Seven in Absentia Homolog 2 in Cholangiocarcinoma Enhances T-Cell–Mediated Antitumor Activity

Frontiers in Immunology

Immunology

Zhi-qing Duan¹  Lu Fang¹  Wen-juan Zheng¹  Fan Zhou¹  Yi-nuo Zhang¹  Bo-ning Chen¹  Bo Liang¹  Hao Zheng²  Liu Ouyang³  Gang Jin³  Zhi-ping Huang⁴  Yuan-ping Tao⁵  Le Yang⁵  Dai-min Xiang⁶  Zhen-guang Wang⁷ 

[1] Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China;Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China;Department of Reproductive Heredity Center, Changhai Hospital, Second Military Medical University, Shanghai, China;Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China;Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China;Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China;Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital of Second Military Medical University, Shanghai, China;Department of Hepatobiliary Surgery, General Hospital of Southern Theatre Command, Guangzhou, China;National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China;State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China;Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China;Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China;

关键词: N6-methyladenosine;    METTL14;    Siah2;    PD-L1;    immunotherapy;   

DOI  :  10.3389/fimmu.2022.845193

 received in 2021-12-29, accepted in 2022-01-10,  发布年份 2022

来源: Frontiers

【 摘 要 】

N6-methyladenosine (m6A) has been reported as an important mechanism of post-transcriptional regulation. Programmed death ligand 1 (PD-L1) is a primary immune inhibitory molecule expressed on tumor cells that promotes immune evasion. In addition, seven in absentia homolog 2 (Siah2), a RING E3 ubiquitin ligase, has been involved in tumorigenesis and cancer progression. However, the role of m6A-METTL14-Siah2-PD-L1 axis in immunotherapy remains to be elucidated. In this study, we showed that METTL14, a component of the m6A methyltransferase complex, induced Siah2 expression in cholangiocarcinoma (CCA). METTL14 was shown to enrich m6A modifications in the 3’UTR region of the Siah2 mRNA, thereby promoting its degradation in an YTHDF2-dependent manner. Furthermore, co-immunoprecipitation experiments demonstrated that Siah2 interacted with PD-L1 by promoting its K63-linked ubiquitination. We also observed that in vitro and in vivo Siah2 knockdown inhibited T cells expansion and cytotoxicity by sustaining tumor cell PD-L1 expression. The METTL14-Siah2-PD-L1–regulating axis was further confirmed in human CCA specimens. Analysis of specimens from patients receiving anti-PD1 immunotherapy suggested that tumors with low Siah2 levels were more sensitive to anti-PD1 immunotherapy. Taken together, our results evidenced a new regulatory mechanism of Siah2 by METTL14-induced mRNA epigenetic modification and the potential role of Siah2 in cancer immunotherapy.

【 授权许可】

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Copyright © 2022 Zheng, Zheng, Wang, Tao, Huang, Yang, Ouyang, Duan, Zhang, Chen, Xiang, Jin, Fang, Zhou and Liang