Ahmed Elshafa Hassan, Lustberg Mark, Hale Claire, Sloan Shelby, Mao Charlene, Zhang Xiaoli, Ozer Hatice Gulcin, Schlotter Sarah, Smith Porsha L, Jeney Frankie, Chan Wing Keung, Harrington Bonnie K, Weigel Christoph, Brooks Eric, Klimaszewski Haley L, Oakes Christopher C, Abebe Tamrat, Ibrahim Muntaser E, Alinari Lapo, Behbehani Gregory K, Shindiapina Polina, Caligiuri Michael A, Baiocchi Robert A
Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA.
Division of Infectious Disease, Department of Internal Medicine, Yale University, New Haven, CT 06520, USA.
Cancers (Basel). 2023 Jun 3;15(11):3046. doi: 10.3390/cancers15113046.
Epstein-Barr virus (EBV) is a ubiquitous herpes virus associated with various cancers. EBV establishes latency with life-long persistence in memory B-cells and can reactivate lytic infection placing immunocompromised individuals at risk for EBV-driven lymphoproliferative disorders (EBV-LPD). Despite the ubiquity of EBV, only a small percentage of immunocompromised patients (~20%) develop EBV-LPD. Engraftment of immunodeficient mice with peripheral blood mononuclear cells (PBMCs) from healthy EBV-seropositive donors leads to spontaneous, malignant, human B-cell EBV-LPD. Only about 20% of EBV+ donors induce EBV-LPD in 100% of engrafted mice (High-Incidence, HI), while another 20% of donors never generate EBV-LPD (No-Incidence, NI). Here, we report HI donors to have significantly higher basal T follicular helper (Tfh) and regulatory T-cells (Treg), and depletion of these subsets prevents/delays EBV-LPD. Transcriptomic analysis of CD4+ T cells from ex vivo HI donor PBMC revealed amplified cytokine and inflammatory gene signatures. HI vs. NI donors showed a marked reduction in IFNγ production to EBV latent and lytic antigen stimulation. In addition, we observed abundant myeloid-derived suppressor cells in HI donor PBMC that decreased CTL proliferation in co-cultures with autologous EBV+ lymphoblasts. Our findings identify potential biomarkers that may identify individuals at risk for EBV-LPD and suggest possible strategies for prevention.
爱泼斯坦-巴尔病毒（EBV）是一种普遍存在的疱疹病毒，与多种癌症相关。EBV在记忆B细胞中建立潜伏感染并终身持续存在，并且可以重新激活裂解感染，使免疫功能低下的个体有患EBV驱动的淋巴增殖性疾病（EBV-LPD）的风险。尽管EBV普遍存在，但只有一小部分免疫功能低下的患者（约20%）会发生EBV-LPD。用来自健康EBV血清阳性供体的外周血单个核细胞（PBMC）移植免疫缺陷小鼠会导致自发性、恶性的人类B细胞EBV-LPD。只有约20%的EBV阳性供体在100%的移植小鼠中诱导出EBV-LPD（高发生率，HI），而另外20%的供体从未产生EBV-LPD（无发生率，NI）。在此，我们报告HI供体具有显著更高的基础滤泡辅助性T细胞（Tfh）和调节性T细胞（Treg），并且这些亚群的耗竭可预防/延迟EBV-LPD。对来自体外HI供体PBMC的CD4+T细胞进行转录组分析，发现细胞因子和炎症基因特征增强。HI供体与NI供体相比，对EBV潜伏和裂解抗原刺激的IFNγ产生明显减少。此外，我们在HI供体PBMC中观察到大量髓源性抑制细胞，这些细胞在与自体EBV阳性淋巴母细胞共培养时会降低CTL增殖。我们的研究结果确定了可能识别有EBV-LPD风险个体的潜在生物标志物，并提出了可能的预防策略。
