Xiong Jie, Dai Yu-Ting, Wang Wen-Fang, Zhang Hao, Wang Chao-Fu, Yin Tong, Cheng Shu, Zhong Hui-Juan, Yu Shan-He, Jiang Lu, Wang Sheng-Yue, Fang Hai, Zhang Rui-Hong, Zhu Yue, Yi Hong-Mei, Jiang Xu-Feng, Chen Jia-Yi, Wang Li, Xu Peng-Peng, Chen Sai-Juan, Zhao Wei-Li
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
Sci Bull (Beijing). 2023 Nov 15;68(21):2607-2619. doi: 10.1016/j.scib.2023.09.029. Epub 2023 Sep 22.
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.
爱泼斯坦-巴尔病毒（EBV）是多种癌症的致癌驱动因素。然而，在疾病发病机制中病毒与癌症免疫相互作用的潜在机制仍 largely 难以捉摸。在此，我们报告了自然杀伤/T细胞淋巴瘤（NKTCL）的首个全面的蛋白质基因组特征，NKTCL是研究EBV诱导淋巴瘤发生的代表性疾病模型，纳入了基因组、转录组和深入的蛋白质组数据。我们对NKTCL的多组学分析表明，EBV基因模式与免疫相关致癌信号相关。单细胞转录组进一步将肿瘤微环境描绘为免疫炎症、免疫缺陷和免疫荒漠表型，与癌症免疫循环的不同设定点相关。EBV与转录因子相互作用以引发GPCR相互作用组（GPCRome）重编程。趋化因子受体-1（CCR1）在恶性和免疫抑制细胞上的表达增强调节了微环境中病毒与癌症的相互作用。靶向CCR1治疗在NKTCL类器官中显示出有前景的疗效，包括清除EBV、激活T细胞和杀死淋巴瘤细胞。总体而言，我们的研究确定了一种先前未知的GPCR介导的恶性进展，并将病毒分子传感器转化为EBV特异性抗癌疗法。
