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

作　　者：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 

机构地区：[1]Liver Cancer Institute,Zhongshan Hospital,Fudan University,Shanghai 200032,China [2]Key Laboratory of Carcinogenesis and Cancer Invasion,Fudan University,Ministry of Education,Shanghai,200032,China [3]State Key Laboratory of Genetic Engineering,Fudan University,Shanghai,200032,China [4]Department of Liver Surgery and Transplantation,Zhongshan Hospital,Fudan University,Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education,Shanghai,China [5]Research Unit of Liver Cancer Recurrence and Metastasis,Chinese Academy of Medical Sciences,Beijing,China [6]Department of Radiation Oncology,Zhongshan Hospital,Fudan University,Shanghai,China [7]Department of General Surgery,Zhongshan Hospital,Fudan University,Shanghai,200032,China

出　　处：《Cellular & Molecular Immunology》2024年第12期1505-1521,共17页中国免疫学杂志(英文版)

基　　金：supported by the National Natural Science Foundation of China(No.82372946,No.82072670,and No.81871916);the Leading Project of the Science and Technology Committee of Shanghai Municipality(No.21Y21900100);the Project of Shanghai Municipal Health Commission(No.202140269).

摘　　要：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.

关 键 词：GSDME IMMUNOTHERAPY MACROPHAGES Hepatocellular carcinomas 

分 类 号：R735.7[医药卫生—肿瘤]