Anti-EBI3 heptapeptide(Tianjin Medical University General Hospital)

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.