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

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外文摘要：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.

外文关键词：

Nuclear PIGLcMycPD-1 antibodyCCL2/20Tumor immune evasion

作者：

Hua Yu、Tiezhu Shi、Linli Yao、Dongwei Xu、Yufeng Ding、Qiang Xia、Wei Liu、Xiongjun Wang

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作者单位：

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

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

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

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

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基金：

Guangdong Natural Science Foundation of Guangdong Province of ChinaNSFCNSFCNSFCScience and Technology Program of Guangdong Province

项目编号：

2021B15150200168200061682272714821731492020B1212060019

出版年：

2023

DOI：

10.1038/s41423-023-01048-3

中国免疫学杂志(英文版)

中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI

影响因子：0.731

ISSN：1672-7681

年,卷(期)：2023.20(8)

参考文献量44