High expression of CXCL13 predicts a favorable response to immunotherapy by upregulating CXCR5+CD8+ T-cell infiltration in gastric cancer.

Introduction: Identifying predictive biomarkers for immune checkpoint inhibitor (ICI) treatment is critical for gastric cancer (GC) prognosis. C-X-C motif chemokine ligand 13(CXCL13) plays an important role in immune regulation by binding exclusively to its receptor CXCR5. However, its role, underlying mechanisms, and prognostic significance in ICI-treated GC patients remain controversial. Methods: This study investigated the clinical significance of CXCL13 and its potential immunomodulatory function in GC patients. A total of 144 GC patients from two cohorts, who received a combination of chemotherapy and anti-PD-1 antibody, were analyzed. The expression of CXCL13 was assessed using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay. Associations between CXCL13, CXCR5, CD8, and CD4 were assessed by IHC and immunofluorescence. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards model. The treatment response to CXCL13 and anti-PD-1 antibody was investigated using a subcutaneous xenograft tumor mouse model. Results: The results suggested that patients with high CXCL13 expression had prolonged survival. High CXCL13 expression exhibited increased infiltration of CXCR5+CD8+ T cells and was associated with better outcomes. The combined assessment of CXCL13, CXCR5, and CD8+ T cells served as an independent predictor of prognosis. Additionally, CXCR5 and CD8+ T cells were enriched in tertiary lymphoid structures (TLSs), which conferred a prognostic benefit in the presence of high CXCL13 expression. CXCL13, in combination with anti-PD-1 therapy, retarded tumor growth in vivo, resulting in increased infiltration of CXCR5+CD8+ T cells. Discussion: This study identified CXCL13 as a prognostic factor in GC patients receiving ICI therapy, emphasizing its critical role in the antitumor microenvironment via CXCR5+CD8+ T cells.