Predictive value of CLDN18.2 ⁺ CD8 ⁺ T cells in peripheral blood and tumor tissue for immunotherapy response and survival in gastric and pancreatic cancers.

Abstract

750 Background: CLDN18.2 has emerged as a therapeutic target in gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC). Recent evidence indicates that CLDN18.2 can be acquired by CD8 + T cells via trogocytosis, leading to impaired cytotoxicity, metabolic dysfunction, and systemic immune senescence. This study aims to evaluate the prognostic and predictive value of CLDN18.2 + CD8 + T cells in peripheral blood and tumor tissues of patients with GC or PDAC receiving immunotherapy. Methods: This prospective observational study has enrolled 300 patients with advanced CLDN18.2-positive GC (n=190) or PDAC (n=110) scheduled to receive anti-PD-1-based immunotherapy in Tianjin Medical University Cancer Institute & Hospital. Peripheral blood and tumor biopsies will be collected at baseline and during treatment. CLDN18.2 + CD8 + T cells will be quantified using flow cytometry and multiplex immunohistochemistry. Primary endpoints include objective response rate (ORR). Secondary endpoints include overall survival (OS) and correlation between CLDN18.2 + CD8 + T cell frequency and functional markers. Results: CLDN18.2 + CD8 + T cell levels in tumor and blood were significantly positively correlated (r=0.78, p < 0.001). Non-responders receiving anti-PD-1-based immunotherapy had higher infiltration in both tumor (GC: 18.2% vs. 6.4%, p <0.05; PDAC: 15.7% vs. 5.1%; p < 0.01) and blood (GC: 7.3% vs. 2.9%, p<0.01; PDAC: 6.8% vs. 2.5%; p < 0.01). Patients with high CLDN18.2 + CD8 + T cells had significantly lower ORR (GC: 16% vs. 52%, p<0.01; PDAC: 14% vs. 48%; p < 0.01) and worse OS (GC: HR = 3.2, p < 0.001; PDAC: HR = 3.5, p < 0.001). Dynamic increases in CLDN18.2 + CD8 + T cells during treatment were also predictive of progressive disease. Conclusions: CLDN18.2 + CD8 + T cells serve as a novel biomarker for predicting poor response to immunotherapy and adverse survival outcomes in CLDN18.2-expressing GC and PDAC. Monitoring these cells in peripheral blood and tumor tissue may facilitate early identification of immunotherapy resistance and guide combination strategies targeting the CLDN18.2/β-catenin axis.