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Elevated nuclear PIGL disrupts the cMyc/BRD4 axis and improves PD-1 blockade therapy by dampening tumor immune evasion

Cellular & Molecular Immunology volume 20, pages 867–880 (2023)Cite this article

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Abstract

To improve the efficacy of lenvatinib in combination with programmed death-1 (PD-1) blockade therapy for hepatocellular carcinoma (HCC), we screened the suppressive metabolic enzymes that sensitize HCC to lenvatinib and PD-1 blockade, thus impeding HCC progression. After analysis of the CRISPR‒Cas9 screen, phosphatidylinositol-glycan biosynthesis class L (PIGL) ranked first in the positive selection list. PIGL depletion had no effect on tumor cell growth in vitro but reprogrammed the tumor microenvironment (TME) in vivo to support tumor cell survival. Specifically, nuclear PIGL disrupted the interaction between cMyc/BRD4 on the distant promoter of target genes and thus decreased the expression of CCL2 and CCL20, which are involved in shaping the immunosuppressive TME by recruiting macrophages and regulatory T cells. PIGL phosphorylation at Y81 by FGFR2 abolished the interaction of PIGL with importin α/β1, thus retaining PIGL in the cytosol and facilitating tumor evasion by releasing CCL2 and CCL20. Clinically, elevated nuclear PIGL predicts a better prognosis for HCC patients and presents a positive correlation with CD8 + T-cell enrichment in tumors. Clinically, our findings highlight that the nuclear PIGL intensity or the change in PIGL-Y81 phosphorylation should be used as a biomarker to guide lenvatinib with PD-1 blockade therapy.

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Acknowledgements

The authors thank the Centre for Precise Gene Editing, Guangzhou University for technical support.

Funding

This study was supported mainly by the Guangdong Natural Science Foundation of Guangdong Province of China 2021B1515020016 and in part by NSFC grants No. 82000616, 82272714, 82173149 and Science and Technology Program of Guangdong Province No. 2020B1212060019.

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Author notes

  1. These authors contributed equally: Hua Yu, Tiezhu Shi, Linli Yao, Dongwei Xu.

Authors and Affiliations

  1. Precise Genome Engineering Centre, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China

    Hua Yu, Tiezhu Shi, Yufeng Ding & Xiongjun Wang

  2. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200240, China

    Linli Yao & Xiongjun Wang

  3. Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China

    Dongwei Xu & Qiang Xia

  4. Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, China

    Wei Liu

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Contributions

HY, TZS, LLY, and DWX designed, performed, and analyzed the experiments and prepared the figures. WL and QX provided technical and clinical assistance. XJW and YFD conceived this study and wrote the manuscript, and XJW, WL, and QX revised the manuscript.

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Correspondence to Wei Liu or Xiongjun Wang.

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The authors declared no competing interests.

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The research content and implementation plan of this experiment strictly complied with the Declaration of Helsinki and was approved by the ethics committee of The Third Affiliated Hospital of Sun Yat-sen University (Medical Ethics 2022-02-333-01).

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Yu, H., Shi, T., Yao, L. et al. Elevated nuclear PIGL disrupts the cMyc/BRD4 axis and improves PD-1 blockade therapy by dampening tumor immune evasion. Cell Mol Immunol 20, 867–880 (2023). https://doi.org/10.1038/s41423-023-01048-3

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