M6A‐mediated upregulation of lncRNA TUG1 in liver cancer cells regulates the antitumor response of CD8+ T cells and phagocytosis of macrophages

Author:

Xi Qing12,Yang Guangze3,He Xue4,Zhuang Hao5,Li Li4,Lin Bing4,Wang Lingling4,Wang Xianyang4,Fang Chunqiang4,Chen Qiurui6,Yang Yongjie4,Yu Zhaoan4,Zhang Hao4,Cai Wenqian4,Li Yan4,Shen Han6,Liu Li7,Zhang Rongxin4ORCID

Affiliation:

1. Department of Gastroenterology and Hepatology The First Affiliated Hospital of Guangdong Pharmaceutical University Guangzhou 510080 China

2. School of Biomedical Sciences and Engineering South China University of Technology Guangzhou 511442 China

3. Laboratory of Immunology and Inflammation Department of Immunology Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China Tianjin Medical University Tianjin 300070 China

4. Laboratory of Immunology and Inflammation Department of Biotechnology School of Life Sciences and Biopharmaceutics Guangdong Provincial Key Laboratory of Advanced Drug Delivery Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System Guangdong Pharmaceutical University Guangzhou 51006 China

5. Department of Hepatobiliopancreatic Surgery The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital Zhengzhou 450008 China

6. Department of Bioscience School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University Guangzhou 51006 China

7. Department of Radiology The University of Texas Southwestern Medical Center 5323 Harry Hines Blvd. Dallas TX 75390 USA

Abstract

AbstractTumor immune evasion relies on the crosstalk between tumor cells and adaptive/innate immune cells. Immune checkpoints play critical roles in the crosstalk, and immune checkpoint inhibitors have achieved promising clinical effects. The long non‐coding RNA taurine‐upregulated gene 1 (TUG1) is upregulated in hepatocellular carcinoma (HCC). However, how TUG1 is upregulated and the effects on tumor immune evasion are incompletely understood. Here, METTL3‐mediated m6A modification led to TUG1 upregulation is demonstrated. Knockdown of TUG1 inhibited tumor growth and metastasis, increased the infiltration of CD8+ T cells and M1‐like macrophages in tumors, promoted the activation of CD8+ T cells through PD‐L1, and improved the phagocytosis of macrophages through CD47. Mechanistically, TUG1 regulated PD‐L1 and CD47 expressions by acting as a sponge of miR‐141 and miR‐340, respectively. Meanwhile, TUG1 interacted with YBX1 to facilitate the upregulation of PD‐L1 and CD47 transcriptionally, which ultimately regulated tumor immune evasion. Clinically, TUG1 positively correlated with PD‐L1 and CD47 in HCC tissues. Moreover, the combination of Tug1‐siRNA therapy with a Pdl1 antibody effectively suppressed tumor growth. Therefore, the mechanism of TUG1 in regulating tumor immune evasion is revealed and can inform existing strategies targeting TUG1 for enhancing HCC immune therapy and drug development.

Funder

National Natural Science Foundation of China

Publisher

Wiley

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