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

Autor: Chen S; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China.; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China., Zhang P; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China.; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China., Zhu G; Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.; Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China., Wang B; Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China., Cai J; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China.; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China., Song L; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China.; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China., Wan J; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China.; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China., Yang Y; Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China., Du J; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China., Cai Y; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China., Zhou J; Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.; Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China., Fan J; Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.; Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China., Dai Z; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China. dai.zhi@zs-hospital.sh.cn.; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China. dai.zhi@zs-hospital.sh.cn.
Jazyk: angličtina
Zdroj: Cellular & molecular immunology [Cell Mol Immunol] 2024 Dec; Vol. 21 (12), pp. 1505-1521. Date of Electronic Publication: 2024 Nov 04.
DOI: 10.1038/s41423-024-01231-0
Abstrakt: 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.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to CSI and USTC.)
Databáze: MEDLINE
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