Elevated nuclear PIGL disrupts the cMyc/BRD4 axis and improves PD-1 blockade therapy by dampening tumor immune evasion
作者机构：Precise Genome Engineering CentreSchool of Life SciencesGuangzhou UniversityGuangzhou510006China State Key Laboratory of Systems Medicine for CancerShanghai Cancer InstituteRen Ji HospitalShanghai Jiaotong University School of MedicineShanghai200240China Department of Liver SurgeryRenji HospitalShanghai Jiaotong University School of MedicineShanghai200127China Guangdong Provincial Key Laboratory of Liver Disease ResearchThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong510630China
出 版 物：《Cellular & Molecular Immunology》 (中国免疫学杂志（英文版）)
年 卷 期：2023年第20卷第8期
页 面：867-880页
核心收录：
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：supported mainly by the Guangdong Natural Science Foundation of Guangdong Province of China 2021B1515020016 in part by NSFC grants No.82000616,82272714,82173149 Science and Technology Program of Guangdong Province No.2020B1212060019
主 题：Nuclear PIGL cMyc PD-1 antibody CCL2/20 Tumor immune evasion
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 *** analysis of the CRISPR‒Cas9 screen,phosphatidylinositol-glycan biosynthesis class L(PIGL)ranked first in the positive selection *** depletion had no effect on tumor cell growth in vitro but reprogrammed the tumor microenvironment(TME)in vivo to support tumor cell ***,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 *** phosphorylation at Y81 by FGFR2 abolished the interaction of PIGL with importinα/β1,thus retaining PIGL in the cytosol and facilitating tumor evasion by releasing CCL2 and ***,elevated nuclear PIGL predicts a better prognosis for HCC patients and presents a positive correlation with CD8+T-cell enrichment in ***,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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