Work

An EBNA1-YAP signaling axis drives immune escape through CD276 in EBV-associated gastric cancer

Year: 2025

Type: article

Abstract: Clinical efficacy of anti-PD1 immunotherapy often yields low response rates in Epstein-Barr virus-associated gastric cancer (EBVaGC). To gain insights into immune escape mechanisms and discover critical molecules in anti-tumor immunity, we performed an immune checkpoint screening using transcriptome profiling and immunohistochemistry analyses. We identified CD276 as an independent immunosuppressive molecule that correlates with poor EBVaGC prognosis. Our in vitro and in vivo experiments demonstrate the role of CD276 in inducing T cell apoptosis and diminishing chemokine secretion, thereby dampening immune response and facilitating tumor progression. Mechanistically, we discovered that YAP/TEAD4 chromatin occupancy at CD276 regulatory regions leads to its transcriptional upregulation in EBVaGC, driven by EBNA1-stimulated MST1/2-LATS1/2-YAP signaling. Notably, in a humanized xenograft mouse model, EBVaGC with elevated CD276 levels exhibited resistance to anti-PD1 immunotherapy, while targeting CD276 in combination with PD1 blockade significantly reduced tumor size. Collectively, our findings elucidate the EBNA1-YAP-CD276 axis as a novel mechanism of immune escape in EBVaGC, providing insights for enhanced immunotherapeutic strategies.

Source: Cell Death and Disease

DOI: 10.1038/s41419-025-08251-2

Authors: Binhao Huang, Mengqi Liu, Yantao Duan, Jing Guo, Zixian Wang, Yi Dou, Mengyun Wang, Omar Abuhaidar, Henian Sun, Leung Siu Kee, Yu Wang, Gong-Hong Wei, Dazhi Xu