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Original research
Targeting tumour-intrinsic N7-methylguanosine tRNA modification inhibits MDSC recruitment and improves anti-PD-1 efficacy
  1. Haining Liu1,
  2. Xuezhen Zeng1,2,
  3. Xuxin Ren3,
  4. Yifan Zhang1,
  5. Manling Huang2,3,
  6. Li Tan1,
  7. Zihao Dai1,
  8. Jiaming Lai1,
  9. Wenxuan Xie1,
  10. Zebin Chen1,
  11. Sui Peng2,4,5,
  12. Lixia Xu2,3,
  13. Shuling Chen2,6,
  14. Shunli Shen1,
  15. Ming Kuang1,2,7,
  16. Shuibin Lin2,8
  1. 1Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  2. 2Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  3. 3Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  4. 4Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  5. 5Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  6. 6Division of Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  7. 7Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, Guangdong, China
  8. 8Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  1. Correspondence to Professor Shuibin Lin, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; linshb6{at}mail.sysu.edu.cn; Professor Ming Kuang, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; kuangm{at}mail.sysu.edu.cn; Professor Shunli Shen, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; shenshli{at}mail.sysu.edu.cn

Abstract

Objective Intrahepatic cholangiocarcinoma (ICC) exhibits very low response rate to immune checkpoint inhibitors (ICIs) and the underlying mechanism is largely unknown. We investigate the tumour immune microenvironment (TIME) of ICCs and the underlying regulatory mechanisms with the aim of developing new target to inhibit tumour growth and improve anti-programmed cell death protein-1 (PD-1) efficacy.

Design Tumour tissues from patients with ICC together with hydrodynamic ICC mouse models were employed to identify the key cell population in TIME of ICCs. Functional analysis and mechanism studies were performed using cell culture, conditional knockout mouse model and hydrodynamic transfection ICC model. The efficacy of single or combined therapy with anti-PD-1 antibody, gene knockout and chemical inhibitor were evaluated in vivo.

Results Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in advanced ICCs and significantly correlated with N7-methylguanosine tRNA methyltransferase METTL1. Using diverse in vivo cancer models, we demonstrate the crucial immunomodulator function of METTL1 in regulation of PMN-MDSC accumulation in TIME and ICC progression. Mechanistically, CXCL8 in human and Cxcl5 in mouse are key translational targets of METTL1 that facilitate its function in promoting PMN-MDSC accumulation in TIME and ICC progression in vivo. Co-blockade of METTL1 and its downstream chemokine pathway enhances the anti-PD-1 efficacy in ICC preclinical mouse models.

Conclusions Our data uncover novel mechanisms underlying chemokine regulation and TIME shaping at the layer of messenger RNA translation level and provide new insights for development of efficient cancer immunotherapeutic strategies.

  • IMMUNOTHERAPY
  • CHOLANGIOCARCINOMA
  • CANCER IMMUNOBIOLOGY
  • CHEMOKINES
  • MOLECULAR MECHANISMS

Data availability statement

Data are available in a public, open access repository. Polysome-mRNA-seq and TRAC-seq data are deposited in GSE214631; Human GSVA data are uploaded as supplemental information.

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Data availability statement

Data are available in a public, open access repository. Polysome-mRNA-seq and TRAC-seq data are deposited in GSE214631; Human GSVA data are uploaded as supplemental information.

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Footnotes

  • HL, XZ, XR, YZ and MH contributed equally.

  • Contributors SL, MK and SS designed the research and obtained funding. SL acts as guarantor for the overall content; HL and XR together with WX and YZ performed in vitro assays. ZD and XZ contributed to the conduct and group allocation of animal experiments and flow cytometry. XR performed in vivo treatment and HL assessed the tumour weight and analysis of the data. LT, MH and SC established the mouse ICC cell line LTP-C9. HL, JL and SL performed polyribosome associated messenger RNA sequencing analysis. HL and SS performed ssGSEA analysis and correlation analysis. ZC, SP and LX developed protocol and coordinated tissue collection. HL and ZD wrote the draft, and all the authors revised and approved the final manuscript.

  • Funding This work was supported by the National Natural Science Foundation of China (grant 82130083 to MK, grants 81922052 and 81974435 to SL, grant 81972587 to SS, grant 82173191 to LX), National key research and development program (YS2022YFA1100191 to SL), the Key Research and Development Plan of Guangzhou City (grant 2022-06-08-04-3001-0010 to MK)

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.