GPCR signaling contributes to immune characteristics of microenvironment and process of EBV-induced lymphomagenesis
Jie Xiong, Yu-Ting Dai, Wenfang Wang, Hao Zhang, Chaofu Wang, Yin Tong, Shu Cheng, Huijuan Zhong, Shanhe Yu, Lu Jiang, Shengyue Wang, Hai Fang, Ruihong Zhang, Yue Zhu, Hongmei Yi, Xufeng Jiang, Jiayi Chen, Li Wang, Pengpeng Xu, Sai‐Juan Chen, Weili Zhao
Abstract
Epstein-Barr virus (EBV) is the oncogenic driver of multiple cancers. However, the underlying mechanism of virus-cancer immunological interaction during disease pathogenesis remains largely elusive. Here we reported the first comprehensive proteogenomic characterization of natural killer/T-cell lymphoma (NKTCL), a representative disease model to study EBV-induced lymphomagenesis, incorporating genomic, transcriptomic, and in-depth proteomic data. Our multi-omics analysis of NKTCL revealed that EBV gene pattern correlated with immune-related oncogenic signaling. Single-cell transcriptome further delineated the tumor microenvironment as immune-inflamed, -deficient, and -desert phenotypes, in association with different setpoints of cancer-immunity cycle. EBV interacted with transcriptional factors to provoke GPCR interactome (GPCRome) reprogramming. Enhanced expression of chemokine receptor-1 (CCR1) on malignant and immunosuppressive cells modulated virus-cancer interaction on microenvironment. Therapeutic targeting CCR1 showed promising efficacy with EBV eradication, T-cell activation, and lymphoma cell killing in NKTCL organoid. Collectively, our study identified a previously unknown GPCR-mediated malignant progression and translated sensors of viral molecules into EBV-specific anti-cancer therapeutics.