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Updated: Jun 29, 2025
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
HSPA4 upregulation induces immune evasion via ALKBH5/CD58 axis in gastric cancer
Daqin Suo1, Xiaoling Gao2, Qingyun Chen3
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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.
Insights
Heat shock protein A4 (HSPA4) upregulation in gastric cancer cells promotes immune evasion by downregulating CD58. HSPA4 upregulation predicts poor survival but better response to immunotherapy in gastric cancer patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Gastric cancer (GC) remains a leading cause of cancer mortality globally.
- While targeted therapies like PD1 antibodies show promise in advanced GC, novel biomarkers for immunotherapy are crucial.
- Understanding GC immune evasion mechanisms is vital for improving treatment strategies.
Purpose of the Study:
- To elucidate the immune evasion mechanisms employed by gastric cancer cells.
- To identify HSPA4 as a potential biomarker for immune checkpoint blockade therapy in GC.
- To investigate the role of HSPA4 in GC progression and treatment response.
Main Methods:
- Coimmunoprecipitation and methylated RNA immunoprecipitation (meRIP) to study molecular mechanisms.
- Coculture systems to assess CD8+ T cell cytotoxicity.
- Multiplex fluorescent immunohistochemistry to analyze HSPA4 expression in GC tissues.
Main Results:
- Histone acetylation leads to HSPA4 upregulation in GC, increasing ALKBH5 stability.
- ALKBH5-mediated m6A regulation decreases CD58 expression in GC cells.
- HSPA4 overexpression impairs CD8+ T cell cytotoxicity and activates the PD1/PDL1 axis.
- HSPA4 upregulation correlates with poorer overall survival in surgically treated GC patients.
- HSPA4 upregulation is observed in responders to anti-PD1 immunotherapy combined with chemotherapy.
Conclusions:
- The HSPA4/ALKBH5/CD58 axis drives GC immune evasion by impairing CD8+ T cell function and activating PD1/PDL1.
- HSPA4 is an independent prognostic factor for worse survival in GC patients undergoing surgery.
- HSPA4 upregulation serves as a predictive biomarker for better response to combined immunotherapy in GC.
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