GPCR信号通路调控微环境的免疫特征和介导EB病毒相关淋巴瘤的发生

GPCR signaling contributes to immune characteristics of microenvironment and process of EBV-induced lymphomagenesis

EB病毒(EBV)是多种肿瘤的致癌驱动因素.然而,肿瘤发生过程中病毒与肿瘤免疫相互作用的潜在机制仍不清楚.自然杀伤T细胞淋巴瘤(NKTCL)是研究EBV相关淋巴瘤发生的代表性疾病模型.本文整合基因组、转录组和蛋白质组数据,全面报道了NKTCL的蛋白质基因组特征.多组学分析发现EBV基因模式与免疫介导的致癌信号相关.单细胞转录组分析进一步描绘肿瘤微环境的免疫炎症、缺陷和沙漠三种表型特征,与肿瘤-免疫循环的不同设定点相关.EBV与转录因子相互作用引起GPCRome重编程,肿瘤细胞和免疫抑制细胞上CCR1的高表达,从而调控微环境中病毒与肿瘤的相互作用.在NKTCL类器官中,靶向CCR1可清除EBV、激活T细胞和杀伤淋巴瘤细胞,具有潜在的靶向治疗作用.综上,本研究首次发现了一种GPCR介导的肿瘤发生发展机制,将病毒分子的感知效应转化为针对EBV的特异性抗肿瘤疗法.

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 GPCRmediated malignant progression and translated sensors of viral molecules into EBV-specific anti-cancer therapeutics.