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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2024

Open Access 01-12-2024 | Gastric Cancer | Research

HSPA4 upregulation induces immune evasion via ALKBH5/CD58 axis in gastric cancer

Authors: Daqin Suo, Xiaoling Gao, Qingyun Chen, Tingting Zeng, Jiarong Zhan, Guanghui Li, Yinli Zheng, Senlin Zhu, Jingping Yun, Xin-Yuan Guan, Yan Li

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

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Abstract

Introduction

Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Recently, targeted therapies including PD1 (programmed cell death 1) antibodies have been used in advanced GC patients. However, identifying new biomarker for immunotherapy is still urgently needed. The objective of this study is to unveil the immune evasion mechanism of GC cells and identify new biomarkers for immune checkpoint blockade therapy in patients with GC.

Methods

Coimmunoprecipitation and meRIP were performed to investigate the mechanism of immune evasion of GC cells. Cocuture system was established to evaluate the cytotoxicity of cocultured CD8+ T cells. The clinical significance of HSPA4 upregulation was analyzed by multiplex fluorescent immunohistochemistry staining in GC tumor tissues.

Results

Histone acetylation causes HSPA4 upregulation in GC tumor tissues. HSPA4 upregulation increases the protein stability of m6A demethylase ALKBH5. ALKBH5 decreases CD58 in GC cells through m6A methylation regulation. The cytotoxicity of CD8+ T cells are impaired and PD1/PDL1 axis is activated when CD8+ T cells are cocultured with HSPA4 overexpressed GC cells. HSPA4 upregulation is associated with worse 5-year overall survival of GC patients receiving only surgery. It is an independent prognosis factor for worse survival of GC patients. In GC patients receiving the combined chemotherapy with anti-PD1 immunotherapy, HSPA4 upregulation is observed in responders compared with non-responders.

Conclusion

HSPA4 upregulation causes the decrease of CD58 in GC cells via HSPA4/ALKBH5/CD58 axis, followed by PD1/PDL1 activation and impairment of CD8+ T cell’s cytotoxicity, finally induces immune evasion of GC cells. HSPA4 upregulation is associated with worse overall survival of GC patients with only surgery. Meanwhile, HSPA4 upregulation predicts for better response in GC patients receiving the combined immunotherapy.
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Metadata
Title
HSPA4 upregulation induces immune evasion via ALKBH5/CD58 axis in gastric cancer
Authors
Daqin Suo
Xiaoling Gao
Qingyun Chen
Tingting Zeng
Jiarong Zhan
Guanghui Li
Yinli Zheng
Senlin Zhu
Jingping Yun
Xin-Yuan Guan
Yan Li
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-024-03029-4

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