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

This study systematically investigates the dynamic modulation of CLDN18.2 expression in gastric cancer patients and its association with tumor microenvironment (TME) remodeling, offering novel insights into targeted immunotherapy strategies.

 

Literature Overview
The 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 relationship with TME remodeling during gastric cancer treatment. The study employed a prospective single-arm phase II clinical trial design, analyzing serial tumor biopsies from advanced gastric cancer patients receiving first-line chemotherapy (capecitabine/oxaliplatin) combined with pembrolizumab.

Background Knowledge
Gastric cancer (GC), a highly heterogeneous disease, has seen significant therapeutic transformation in recent years due to immunotherapy. Claudin 18.2 (CLDN18.2) represents a promising target for GC treatment as it maintains stable expression during malignant transformation while being specifically localized to gastric cancer cells. Although zolbetuximab demonstrates clinical benefits in CLDN18.2-positive GC, the dynamic expression patterns of CLDN18.2 during chemo-immunotherapy and its impact on TME remain incompletely understood. The gastric TME exhibits remarkable complexity, characterized by immune cell infiltration, stromal remodeling, and activated transforming growth factor-beta (TGF-β) signaling pathways, which may influence therapeutic responses and drug resistance mechanisms. This study utilized 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, thereby providing theoretical foundations for optimizing CLDN18.2-targeted therapies.

 

 

Research Methods and Experiments
The research team evaluated serial tumor biopsies from advanced gastric cancer patients treated with first-line chemotherapy (capecitabine/oxaliplatin) combined with pembrolizumab in a prospective single-arm phase II clinical trial. CLDN18.2 expression levels were determined through immunohistochemistry (IHC), while TME molecular characteristics 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 subpopulation profiling, and expression pattern changes of cytokines and signaling pathways.

Key Conclusions and Perspectives

• Among 57 patients, 40.4% demonstrated CLDN18.2 positivity at baseline. CLDN18.2 positivity correlated with diffuse-type gastric cancer, high PD-L1 expression, and immune-inflammatory microenvironments rich in T cells and stromal components.
• Gene set enrichment analysis revealed significant upregulation of immune activation and stromal remodeling genes in CLDN18.2-positive tumors, particularly those involved in TGF-β signaling and extracellular matrix remodeling.
• Single-cell analysis identified increased regulatory T cell (Treg) populations and activated Galectin-3-CD44 signaling pathways in CLDN18.2-positive tumors.
• Following one chemotherapy cycle, 40% of initially CLDN18.2-positive tumors lost expression while 10% of initially negative tumors acquired expression, particularly in patients with fibrotic TME.
• While overall survival (OS) showed no significant difference between CLDN18.2-positive and negative groups, patients with double-negative status for CLDN18.2 and PD-L1 exhibited poorer prognosis.

Research Significance and Prospects
This study represents the first systematic analysis of CLDN18.2 dynamic changes during gastric cancer treatment and their association with TME remodeling. It emphasizes the importance of repeated biomarker assessment and suggests combination therapeutic strategies targeting both epithelial and stromal compartments may enhance treatment efficacy. Future research should investigate the Galectin-3-CD44 axis role in CLDN18.2-positive gastric cancer immune evasion and evaluate its potential as a therapeutic target.

 

 

Conclusion
This study demonstrates that CLDN18.2 expression exhibits significant dynamics during chemo-immunotherapy in gastric cancer patients, with changes closely linked to TME remodeling. These findings suggest clinical monitoring of CLDN18.2 as a dynamic biomarker is essential for optimizing targeted therapy strategies. Furthermore, CLDN18.2-positive tumors exhibit distinct immunosuppressive and fibrotic microenvironmental features, necessitating combination therapies to overcome drug resistance. These results provide crucial molecular and cellular foundations for further optimizing gastric cancer immunotherapy and developing personalized treatment approaches.

 

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.