M 6 A Demethylase ALKBH5 Regulates PD-L1 Expression and Tumor Immunoenvironment in Intrahepatic Cholangiocarcinoma

• Published in: Cancer research (Chicago, Ill.) Vol. 81; no. 18; p. 4778
• Main Authors: Qiu, Xinyao, Yang, Shuai, Wang, Shan, Wu, Jianmin, Zheng, Bo, Wang, Kaiting, Shen, Siyun, Jeong, Seogsong, Li, Zhixuan, Zhu, Yanjing, Wu, Tong, Wu, Xuan, Wu, Rui, Liu, Weiwei, Wang, Hong-Yang, Chen, Lei
• Format: Journal Article
• Language: English
• Published: United States 15.09.2021
• Subjects: AlkB Homolog 5, RNA Demethylase - metabolism; Animals; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Bile Duct Neoplasms - etiology; Bile Duct Neoplasms - metabolism; Bile Duct Neoplasms - pathology; Cell Line, Tumor; Cholangiocarcinoma - etiology; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - pathology; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Immunomodulation; Mice; Protein Binding; RNA Stability; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tumor Microenvironment - genetics; Tumor Microenvironment - immunology
• ISSN: 1538-7445

N -methyladenosine (m A) has been reported as an important mechanism of posttranscriptional regulation. Programmed death-ligand 1 (PD-L1) is a primary immune inhibitory molecule expressed on tumor cells that promotes immune evasion. Here we report ALKBH5 as an important m A demethylase that orchestrates PD-L1 expression in intrahepatic cholangiocarcinoma (ICC). Regulation of PD-L1 expression by ALKBH5 was confirmed in human ICC cell lines. Sequencing of the m A methylome identified PD-L1 mRNA as a direct target of m A modification whose levels were regulated by ALKBH5. Furthermore, ALKBH5 and PD-L1 mRNA were shown to interact. ALKBH5 deficiency enriched m A modification in the 3'UTR region of PD-L1 mRNA, thereby promoting its degradation in a YTHDF2-dependent manner. and , tumor-intrinsic ALKBH5 inhibited the expansion and cytotoxicity of T cells by sustaining tumor cell PD-L1 expression. The ALKBH5-PD-L1-regulating axis was further confirmed in human ICC specimens. Single-cell mass cytometry analysis unveiled a complex role of ALKBH5 in the tumor immune microenvironment by promoting the expression of PD-L1 on monocytes/macrophages and decreasing the infiltration of myeloid-derived suppressor-like cells. Analysis of specimens from patients receiving anti-PD1 immunotherapy suggested that tumors with strong nuclear expression patterns of ALKBH5 are more sensitive to anti-PD1 immunotherapy. Collectively, these results describe a new regulatory mechanism of PD-L1 by mRNA epigenetic modification by ALKBH5 and the potential role of ALKBH5 in immunotherapy response, which might provide insights for cancer immunotherapies. SIGNIFICANCE: This study identifies PD-L1 mRNA as a target of ALKBH5 and reveals a role for ALKBH5 in regulating the tumor immune microenvironment and immunotherapy efficacy.