Dynamic modulation of claudin18.2 expression and remodeling of the tumor microenvironment in gastric cancer during chemo-immunotherapy.
[BACKGROUND] Claudin 18.2 (CLDN18.2) is a tight junction protein retained in malignant transformation of gastric cancer (GC) and is a promising therapeutic target.
APA
Lim SH, Kuwata T, et al. (2025). Dynamic modulation of claudin18.2 expression and remodeling of the tumor microenvironment in gastric cancer during chemo-immunotherapy.. Journal for immunotherapy of cancer, 13(9). https://doi.org/10.1136/jitc-2025-012683
MLA
Lim SH, et al.. "Dynamic modulation of claudin18.2 expression and remodeling of the tumor microenvironment in gastric cancer during chemo-immunotherapy.." Journal for immunotherapy of cancer, vol. 13, no. 9, 2025.
PMID
41027671
Abstract
[BACKGROUND] Claudin 18.2 (CLDN18.2) is a tight junction protein retained in malignant transformation of gastric cancer (GC) and is a promising therapeutic target. Despite the clinical benefit of zolbetuximab in CLDN18.2-positive tumors, the dynamic expression of CLDN18.2 during chemoimmunotherapy and its implications in the tumor microenvironment (TME) remain poorly understood.
[METHODS] In a prospective single-arm phase II trial, we evaluated serial tumor biopsies from patients with advanced GC receiving first-line chemotherapy (capecitabine/oxaliplatin) with sequential pembrolizumab. CLDN18.2 expression was assessed by immunohistochemistry, and integrated molecular analyses-including whole transcriptome, whole exome, and single-cell RNA sequencing-were performed to explore TME alterations and molecular correlates.
[RESULTS] Among 57 patients, 40.4% were CLDN18.2-positive at baseline. CLDN18.2 positivity was associated with diffuse-type histology, higher programmed death-ligand 1 (PD-L1) combined positive scores, and an immune-inflamed, stroma-rich TME characterized by enhanced T cell infiltration, transforming growth factor-β signaling, and matrix remodeling. Gene set enrichment analyses revealed immune activation and stromal remodeling in CLDN18.2-positive tumors. Single-cell analysis showed increased regulatory T cells and galectin-3-CD44 signaling in CLDN18.2-positive tumors. After one cycle of chemotherapy, CLDN18.2 expression was lost in 40% of initially positive tumors, while 10% of initially negative tumors gained expression-particularly in fibrotic TMEs. Survival outcomes were not significantly different between CLDN18.2-positive and CLDN18.2-negative groups; however, patients negative for both CLDN18.2 and PD-L1 showed poorer prognosis.
[CONCLUSIONS] CLDN18.2 expression is dynamically regulated during chemoimmunotherapy and is associated with a distinct immunosuppressive and fibrotic TME. These findings highlight the importance of repeated biomarker assessment and suggest potential combinatorial therapeutic strategies targeting both epithelial and stromal compartments in GC.
[TRIAL REGISTRATION NUMBER] NCT04249739.
[METHODS] In a prospective single-arm phase II trial, we evaluated serial tumor biopsies from patients with advanced GC receiving first-line chemotherapy (capecitabine/oxaliplatin) with sequential pembrolizumab. CLDN18.2 expression was assessed by immunohistochemistry, and integrated molecular analyses-including whole transcriptome, whole exome, and single-cell RNA sequencing-were performed to explore TME alterations and molecular correlates.
[RESULTS] Among 57 patients, 40.4% were CLDN18.2-positive at baseline. CLDN18.2 positivity was associated with diffuse-type histology, higher programmed death-ligand 1 (PD-L1) combined positive scores, and an immune-inflamed, stroma-rich TME characterized by enhanced T cell infiltration, transforming growth factor-β signaling, and matrix remodeling. Gene set enrichment analyses revealed immune activation and stromal remodeling in CLDN18.2-positive tumors. Single-cell analysis showed increased regulatory T cells and galectin-3-CD44 signaling in CLDN18.2-positive tumors. After one cycle of chemotherapy, CLDN18.2 expression was lost in 40% of initially positive tumors, while 10% of initially negative tumors gained expression-particularly in fibrotic TMEs. Survival outcomes were not significantly different between CLDN18.2-positive and CLDN18.2-negative groups; however, patients negative for both CLDN18.2 and PD-L1 showed poorer prognosis.
[CONCLUSIONS] CLDN18.2 expression is dynamically regulated during chemoimmunotherapy and is associated with a distinct immunosuppressive and fibrotic TME. These findings highlight the importance of repeated biomarker assessment and suggest potential combinatorial therapeutic strategies targeting both epithelial and stromal compartments in GC.
[TRIAL REGISTRATION NUMBER] NCT04249739.
MeSH Terms
Humans; Stomach Neoplasms; Tumor Microenvironment; Claudins; Female; Male; Middle Aged; Aged; Immunotherapy; Prospective Studies; Antineoplastic Combined Chemotherapy Protocols; Adult
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