2. Academic Validation
  3. Proton pump inhibitors stabilize the expression of PD-L1 on cell membrane depending on the phosphorylation of GSK3β

Proton pump inhibitors stabilize the expression of PD-L1 on cell membrane depending on the phosphorylation of GSK3β

  • Cancer Med. 2024 May;13(10):e7083. doi: 10.1002/cam4.7083.
Long Gao 1,  Yuan Liu 2,  Jiaying Liu 1,  Jiali Li 1,  Haotian Li 1,  Yanyan Liu 1,  Fang Meng 3 4,  Xiaohong Du 3 4 5,  Yufeng Gao 1,  Jiabin Li 1,  F Xiao-Feng Qin 3 4
Affiliations

Affiliations

  • 1 Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 2 Market Supervision Administration of Xiangcheng District, Suzhou, China.
  • 3 National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, Jiangsu, China.
  • 4 Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, Jiangsu, China.
  • 5 Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, China.
PMID: 38752436 DOI: 10.1002/cam4.7083
Abstract

Background: Preclinical and clinical evidence indicates that Proton Pump inhibitors (PPIs) may indirectly diminish the microbiome diversity, thereby reducing the effectiveness of immune checkpoint inhibitors (ICIs). Conversely, recent publications have shown that PPIs could potentially enhance the response to ICIs. The precise mechanism through which PPIs modulate the ICIs remains unclear. In this study, we discovered a novel molecular function of PPIs in regulating immune invasion, specifically through inducing PD-L1 translocation in various tumor cells.

Methods: C57BL/6 mice subcutaneous transplantation model is used to verify the potential efficacy of PPIs and PD-L1 antibody. Western blotting analysis and phosphorylated chip are used to verify the alteration of PD-L1-related pathways after being treated with PPIs. The related gene expression is performed by qRT-PCR and luciferase reporter analysis. We also collected 60 clinical patients diagnosed with esophageal Cancer or reflux esophagitis and then detected the expression of PD-L1 in the tissue samples by immunohistochemistry.

Results: We observed that the IC50 of tumor cells in response to PPIs was significantly higher than that of normal epithelial cells. PPIs significantly increased the expression of PD-L1 on cell membrane at clinically relevant concentrations. Furthermore, pre-treatment with PPIs appeared to synergize the efficiency of anti-PD-L1 Antibodies in mouse models. However, PPI administration did not alter the transcription or total protein level of PD-L1 in multiple tumor cells. Using a phosphorylated protein chip, we identified that PPIs enhanced the phosphorylation of GSK3β, then leading to PD-L1 protein translocation to the cell membranes. The capacity of PPIs to upregulate PD-L1 was negated following GSK3β knockout. Furthermore, our clinical data showed that the PPIs use resulted in increased PD-L1 expression in esophageal Cancer patients.

Conclusion: We mainly address a significant and novel mechanism that the usage of PPIs could directly induce the expression of PD-L1 by inducing GSK3β phosphorylation and facilitate primary tumor progression and metastasis.

Keywords

GSK3β; PD‐L1; immune checkpoint inhibitors; proton pump inhibitors.

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