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

## TL;DR

This study identifies a new immune escape mechanism in Epstein-Barr virus-associated gastric cancer involving CD276, offering potential for improved immunotherapy.

## Contribution

The discovery of the EBNA1-YAP-CD276 signaling axis as a novel immune escape mechanism in EBV-associated gastric cancer.

## Key findings

- CD276 is an independent immunosuppressive molecule linked to poor prognosis in EBV-associated gastric cancer.
- CD276 induces T cell apoptosis and reduces chemokine secretion, weakening immune responses and promoting tumor growth.
- Targeting CD276 combined with PD1 blockade significantly reduces tumor size in a mouse model.

## 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.