Ubiquilin-4 induces immune escape in gastric cancer by activating the notch signaling pathway.

Purpose: We aimed to investigate the role of ubiquilin-4 in predicting the immunotherapy response in gastric cancer.

Methods: Retrospective RNA-sequencing and immunohistochemical analysis were performed for patients with gastric cancer who received programmed death-1 blockade therapy after recurrence. Multiplex immunohistochemistry identified immune cell types in gastric cancer tissues. We used immunocompetent 615 mice and immunodeficient nude mice to perform tumorigenic experiments.

Results: Ubiquilin-4 expression was significantly higher in responders (p < 0.05, false discovery rate > 2.5) and showed slight superiority over programmed death ligand 1 in predicting programmed death-1 inhibitor therapy response (area under the curve: 87.08 vs. 72.50). Ubiquilin-4-high patients exhibited increased CD4⁺ and CD8⁺ T cells, T follicular helper cells, monocytes, and macrophages. Ubiquilin-4-overexpressed mouse forestomach carcinoma cells showed significantly enhanced growth in immunocompetent mice but not in immunodeficient mice. Upregulation or downregulation of ubiquilin-4 synergistically affected programmed death ligand 1 at the protein and messenger RNA levels. Functional enrichment analysis revealed significant enrichment of the Notch, JAK-STAT, and WNT signaling pathways in ubiquilin-4-high gastric cancers. Ubiquilin-4 promoted Numb degaration, activating the Notch signaling pathway and upregulating programmed death ligand 1.

Conclusions: Ubiquilin-4 may contribute to immune escape in gastric cancer by upregulating programmed death ligand 1 expression in tumor cells through Notch signaling activation. Thus, ubiquilin-4 could serve as a predictive marker for programmed death ligand 1 inhibitor therapy response in gastric cancer.