Gq/G11 oncogenic mutations promote PD-L1 expression and suppress tumor immunity

Abstract

Uveal melanoma (UM) is the predominant form of eye cancer. The genes GNAQ and GNA11, encoding Gq and G11 respectively, are most frequently mutated in UM and are considered the major drivers of UM carcinogenesis by activating YAP. However, the mechanisms by which metastatic UM evades the immune system remain poorly understood. In this study, we found that oncogenic mutations of Gq/G11 promoted YAP and PD-L1 expression, modifying the tumor microenvironment and promoting immune evasion of UM. Consistently, the levels of GNAQ/GNA11 and YAP positively correlated to PD-L1 expression in UM patients. Furthermore, silencing YAP or treating with its inhibitor, Verteporfin, attenuated PD-L1 expression induced by Gq/G11 mutations, thereby enhancing T cell activation and T cell-mediated cytotoxicity. Collectively, this study reveals a potential role of Gq/G11 mutations on immune evasion of UM, a new mechanism of Gq/11 mutations-induced tumorigenesis, highlighting Gq/G11 and YAP as potential immunotherapeutic targets and suggesting Verteporfin as an adjuvant for immunotherapy of UM patients with GNAQ or GNA11 mutations.