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.
- CANCER IMMUNOBIOLOGY
- 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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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.
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