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

作者：Daqin Suo, Xiaoling Gao, Qingyun Chen, Tingting Zeng, Jiarong Zhan, Guanghui Li, Yinli Zheng, Senlin Zhu, Jing‐Ping Yun, Xin‐Yuan Guan, Yan Li · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2024 · DOI：10.1186/s13046-024-03029-4 · 被引用次数：24 · 研究领域：Cancer Immunotherapy and Biomarkers、HER2/EGFR in Cancer Research、Cancer, Stress, Anesthesia, and Immune Response

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 m 6 A demethylase ALKBH5. ALKBH5 decreases CD58 in GC cells through m 6 A 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 comp...