Targeting GSDME-mediated macrophage polarization for enhanced antitumor immunity in hepatocellular carcinoma.

IF 21.8 1区 医学 Q1 IMMUNOLOGY
Shiping Chen, Peiling Zhang, Guiqi Zhu, Biao Wang, Jialiang Cai, Lina Song, Jinglei Wan, Yi Yang, Junxian Du, Yufan Cai, Jian Zhou, Jia Fan, Zhi Dai
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引用次数: 0

Abstract

Despite the notable efficacy of anti-PD1 therapy in the management of hepatocellular carcinoma (HCC) patients, resistance in most individuals necessitates additional investigation. For this study, we collected tumor tissues from nine HCC patients receiving anti-PD1 monotherapy and conducted RNA sequencing. These findings revealed significant upregulation of GSDME, which is predominantly expressed by tumor-associated macrophages (TAMs), in anti-PD1-resistant patients. Furthermore, patients with elevated levels of GSDME+ macrophages in HCC tissues presented a poorer prognosis. The analysis of single-cell sequencing data and flow cytometry revealed that the suppression of GSDME expression in nontumor cells resulted in a decrease in the proportion of M2-like macrophages within the tumor microenvironment (TIME) of HCC while concurrently augmenting the cytotoxicity of CD8 + T cells. The non-N-terminal fragment of GSDME within macrophages combines with PDPK1, thereby activating the PI3K-AKT pathway and facilitating M2-like polarization. The small-molecule Eliprodil inhibited the increase in PDPK1 phosphorylation mediated by GSDME site 1. The combination of Eliprodil and anti-PD1 was effective in the treatment of both spontaneous HCC in c-Myc + /+;Alb-Cre + /+ mice and in a hydrodynamic tail vein injection model, which provides a promising strategy for novel combined immunotherapy.

靶向 GSDME 介导的巨噬细胞极化,增强肝细胞癌的抗肿瘤免疫力。
尽管抗-PD1疗法在治疗肝细胞癌(HCC)患者方面疗效显著,但大多数患者的耐药性仍需要进一步研究。在这项研究中,我们收集了九名接受抗 PD1 单药治疗的 HCC 患者的肿瘤组织,并进行了 RNA 测序。研究结果显示,抗PD1耐药患者体内主要由肿瘤相关巨噬细胞(TAMs)表达的GSDME明显上调。此外,HCC 组织中 GSDME+ 巨噬细胞水平升高的患者预后较差。对单细胞测序数据和流式细胞术的分析表明,抑制非肿瘤细胞中 GSDME 的表达会降低 HCC 肿瘤微环境(TIME)中 M2 样巨噬细胞的比例,同时增强 CD8 + T 细胞的细胞毒性。巨噬细胞内 GSDME 的非 N 端片段与 PDPK1 结合,从而激活 PI3K-AKT 通路并促进 M2 样极化。小分子 Eliprodil 可抑制由 GSDME 位点 1 介导的 PDPK1 磷酸化的增加。Eliprodil和抗PD1的联合疗法对c-Myc + /+;Alb-Cre + /+小鼠自发性HCC和水动力尾静脉注射模型均有效,这为新型联合免疫疗法提供了一种前景广阔的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
31.20
自引率
1.20%
发文量
903
审稿时长
1 months
期刊介绍: Cellular & Molecular Immunology, a monthly journal from the Chinese Society of Immunology and the University of Science and Technology of China, serves as a comprehensive platform covering both basic immunology research and clinical applications. The journal publishes a variety of article types, including Articles, Review Articles, Mini Reviews, and Short Communications, focusing on diverse aspects of cellular and molecular immunology.
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