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Cellular &Molecular Immunology

Cellular &Molecular Immunology

IF: 19.8
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Targeting GSDME-mediated macrophage polarization for enhanced antitumor immunity in hepatocellular carcinoma

Published:4 November 2024 DOI: 10.1038/s41423-024-01231-0 PMID: 39496854
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

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.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Eliprodil 119431-25-3 C20H23ClFNO 130 suppliers $24.00-$2287.00
Eliprodil 119431-25-3 C20H23ClFNO 130 suppliers $24.00-$2287.00
Eliprodil 119431-25-3 C20H23ClFNO 130 suppliers $24.00-$2287.00
Eliprodil 119431-25-3 C20H23ClFNO 130 suppliers $24.00-$2287.00

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