Tumor-Derived EBI3 Promotes CD8+ T-cell Exhaustion via STAT4-IL10/CCL5 in Gastric Cancer.

Overview

abstract

Combination chemotherapy and immunotherapy are effective against advanced gastric cancer. However, T-cell exhaustion in the tumor microenvironment may decrease the immune response and compromise the effectiveness of immunotherapy. Herein, we report the potential role of EBI3 in promoting T-cell exhaustion and its mechanism in gastric cancer, showing high expression of EBI3 in gastric cancer. Correlation analysis between EBI3 expression level and clinical-pathologic features indicated significant associations with tumor stage, nodal staging, pathologic stage, and degree of tumor differentiation. EBI3 expression levels correlated with a state of high CD8+ T-cell exhaustion, as identified by transcriptome sequencing and mouse orthotopic gastric cancer models. On exposure to EBI3, CD8+ T cells showed signs of cell exhaustion as reduced cytokine secretion and increased expression of inhibitory receptors in in vitro/vivo studies. Mechanistically, EBI3 induced T-cell exhaustion by promoting the phosphorylation of STAT4 and upregulating the transcription of downstream target genes CCL5 and IL10. An anti-EBI3 heptapeptide (Val-Tyr-Leu-His-Trp-His-Asp) was developed, which competitively bound EBI3 and reversed the induction of T-cell exhaustion. Taken together, we identified a T-cell exhaustion mechanism in gastric cancer via the EBI3-STAT4-IL10/CCL5 axis and developed an anti-EBI3 heptapeptide with an antagonistic function. These findings provide a potential immunotherapeutic target and support the development of EBI3-based interventions to enhance immunotherapy efficacy in gastric cancer.