2. Academic Validation
  3. IRGM is a novel regulator of PD-L1 via promoting S6K1-mediated phosphorylation of YBX1 in hepatocellular carcinoma

IRGM is a novel regulator of PD-L1 via promoting S6K1-mediated phosphorylation of YBX1 in hepatocellular carcinoma

  • Cancer Lett. 2023 Nov 20:216495. doi: 10.1016/j.canlet.2023.216495.
Junnan Ru 1,  Jiahua Lu 2,  Jiangzhen Ge 1,  Bo Ding 2,  Rong Su 1,  Yifan Jiang 3,  Yujing Sun 4,  Jun Ma 3,  Yu Li 2,  Jingqi Sun 3,  Guangming Xu 2,  Rongliang Tong 1,  Shusen Zheng 5,  Beng Yang 6,  Jian Wu 7
Affiliations

Affiliations

  • 1 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Zhejiang province, Hangzhou, China.
  • 2 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China.
  • 3 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Zhejiang province, Hangzhou, China.
  • 4 General Practice Department, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 5 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Zhejiang province, Hangzhou, China. Electronic address: shusenzheng@zju.edu.cn.
  • 6 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Zhejiang province, Hangzhou, China. Electronic address: 21518093@zju.edu.cn.
  • 7 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Zhejiang province, Hangzhou, China. Electronic address: drwujian@zju.edu.cn.
PMID: 37993085 DOI: 10.1016/j.canlet.2023.216495
Abstract

Immunity-related GTPase M (IRGM), an Interferon-inducible protein, functions as a pivotal immunoregulator in multiple autoimmune diseases and Infection. However, the role of IRGM in hepatocellular carcinoma (HCC) development remains unveiled. Here, we found interferon-γ (IFN-γ) treatment in HCC drastically triggered the expression of IRGM, and the high level of IRGM indicated poor prognosis in HCC patients. Functionally, IRGM promoted the malignant progression of HCC. Single-cell Sequencing revealed that IRGM inhibition promoted the infiltration of CD8+ cytotoxic T lymphocytes (CTLs) with significant downregulation of PD-L1 expression in HCC. Furthermore, Immunoprecipitation-Mass Spectrometry assay revealed that IRGM interacted with transcription factor YBX1, which facilitated PD-L1 transcription. Mechanistically, IRGM promoted the interaction of YBX1 and phosphokinase S6K1, increasing phosphorylation and nuclear localization of YBX1, transcription of PD-L1. Additionally, the combination of IRGM inhibition with α-PD1 demonstrated a stronger anti-tumor effect compared to the single application of α-PD1. In summary, IRGM is a novel regulator of PD-L1, which suppresses CD8+ CTLs infiltration and function in HCC, resulting in Cancer progression. This study may raise a novel therapeutic strategy combined with Immune Checkpoint inhibitors (ICIs) against HCC.

Keywords

IRGM; Immune therapy; Liver cancer; Programmed death-ligand 1; Tumor microenvironment.

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