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

Abstract Clinical efficacy of anti-PD1 immunotherapy is often with low response rates in Epstein-Barr virus-associated gastric cancer (EBVaGC). To gain insights into the immune escape and discovering the key molecule against anti-tumor immunity, we performed an immune checkpoint screening with transcriptome profiling and IHC staining data. CD276 was found as an independent immune suppressive molecule and correlated with a worse prognosis. Our in vitro and in vivo experiments showed that CD276 promotes T cell apoptosis and reduces its chemokine secretion, thereby attenuating immune response and promoting tumor progression. Mechanistically, we revealed a chromatin occupancy of YAP/TEAD4 at the regulatory regions of CD276 and confirmed YAP/TEAD-mediated transcriptional upregulation of CD276 in EBVaGC. We further revealed that EBNA1 stimulate the MST1/2-LATS1/2-YAP axis, thus acting on the upstream of YAP activation to drive aberrant CD276 overexpression. Intriguingly, we established humanized xenograft mouse model and observed that EBVaGC with CD276 upregulation showed insensitivity to anti-PD1 immunotherapy while targeting CD276 in combination with PD1 blockade could effectively reduce the tumor size. Collectively, we unraveled the EBNA1-YAP-CD276 axis in promoting immune escape, representing a newly-discovered mechanism in EBVaGC with low response rate to anti-PD1 immunotherapy, and provided a novel insight into a potential immunotherapeutic avenue for EBVaGC treatment.