Journal for Immunotherapy of Cancer | Dynamic Modulation of CLDN18.2 Expression and Remodeling of the Immune Microenvironment in Gastric Cancer

This study systematically reveals the dynamic changes of CLDN18.2 expression in gastric cancer patients and its correlation with tumor microenvironment remodeling, providing novel insights for developing targeted immunotherapy strategies.

 

Literature Overview
This article titled 'Dynamic modulation of claudin18.2 expression and remodeling of the tumor microenvironment in gastric cancer during chemo-immunotherapy' published in the Journal for Immunotherapy of Cancer reviews the dynamic regulation of tight junction protein CLDN18.2 and its association with tumor microenvironment (TME) remodeling during gastric cancer treatment. The research employs a prospective single-arm phase II clinical trial design, analyzing serial tumor biopsy samples from advanced gastric cancer patients receiving first-line chemotherapy (capecitabine/oxaliplatin) combined with pembrolizumab therapy.

Background Knowledge
Gastric cancer (GC) is a highly heterogeneous disease whose treatment has been revolutionized by immunotherapy in recent years. Claudin 18.2 (CLDN18.2) is a promising therapeutic target specifically expressed in gastric cancer cells, maintaining stable expression during malignant transformation. Although zolbetuximab demonstrates clinical benefits in CLDN18.2-positive gastric cancer, the dynamic expression patterns of CLDN18.2 during chemo-immunotherapy and its impact on TME remain poorly understood. Additionally, the TME of gastric cancer exhibits high complexity, including immune cell infiltration, stromal remodeling, and activation of transforming growth factor β (TGF-β) signaling pathways, which may influence treatment efficacy and drug resistance mechanisms. This study utilizes multi-omics analyses (including whole transcriptome, whole exome, and single-cell RNA sequencing) to explore TME characteristics in CLDN18.2-positive gastric cancer and their dynamic changes during treatment, establishing a theoretical foundation for optimizing CLDN18.2-targeted therapies.

 

 

Research Methods and Experiments
The research team evaluated serial tumor biopsy samples from advanced gastric cancer patients undergoing first-line chemotherapy (capecitabine/oxaliplatin) combined with pembrolizumab therapy in a prospective single-arm phase II clinical trial. CLDN18.2 expression levels were detected through immunohistochemistry (IHC), while molecular features of TME were analyzed using whole transcriptome, whole exome, and single-cell RNA sequencing technologies. Key research components included gene set enrichment analysis, T cell and myeloid cell subgroup analysis, and expression pattern changes of cytokines and signaling pathways.

Key Conclusions and Perspectives

• Among 57 patients, 40.4% presented CLDN18.2 positivity at baseline. CLDN18.2 positivity correlates with diffuse-type gastric cancer, high PD-L1 expression, and immune-inflamed microenvironment enriched with T cells and stromal components.
• Gene set enrichment analysis demonstrates significant upregulation of immune activation and stromal remodeling-related genes in CLDN18.2-positive tumors, including TGF-β signaling pathway and extracellular matrix remodeling.
• Single-cell analysis reveals increased regulatory T cells (Tregs) and activation of Galectin-3-CD44 signaling pathway in CLDN18.2-positive tumors.
• After one chemotherapy cycle, 40% initial CLDN18.2-positive tumors lose expression while 10% initial negative tumors acquire expression, particularly in patients with fibrotic TME.
• Although overall survival (OS) shows no significant difference between CLDN18.2-positive and negative groups, patients with double-negative status for CLDN18.2 and PD-L1 exhibit poor prognosis.

Research Significance and Prospects
This study provides the first systematic analysis of CLDN18.2 dynamic expression patterns in gastric cancer treatment and their correlation with TME remodeling. It emphasizes the importance of repeated biomarker assessments and suggests combined targeting strategies for epithelial and stromal compartments may improve therapeutic outcomes. Future research should explore the Galectin-3 and CD44 axis in CLDN18.2-positive gastric cancer immune evasion and evaluate their potential as therapeutic targets.

 

 

Conclusion
This study identifies CLDN18.2 expression as highly dynamic during chemo-immunotherapy in gastric cancer patients, with changes closely associated with TME remodeling. These findings suggest clinical monitoring of CLDN18.2 expression dynamics is critical for optimizing targeted treatment strategies. Additionally, CLDN18.2-positive tumors exhibit distinct immunosuppressive and fibrotic microenvironment features requiring combination therapies to overcome drug resistance. These results establish important molecular and cellular foundations for further optimizing gastric cancer immunotherapy and provide evidence for developing future precision treatment protocols.

 

Sung Hee Lim, Takeshi Kuwata, Minae An, Kohei Shitara, and Jeeyun Lee. Dynamic modulation of claudin18.2 expression and remodeling of the tumor microenvironment in gastric cancer during chemo-immunotherapy. Journal for Immunotherapy of Cancer.