肿瘤细胞治疗研究
英文原题：Epstein-Barr Virus-Positive Lymphomas Exploit Ectonucleotidase Activity To Limit Immune Responses and Prevent Cell Death.
Epstein-Barr Virus-Positive Lymphomas Exploit Ectonucleotidase Activity To Limit Immune Responses and Prevent Cell Death.
这些数据共同表明，EBV⁺ B 细胞淋巴瘤利用外核苷酸酶活性来规避 ATP 介导的炎症和细胞死亡。
EB病毒（EBV）是一种与癌症相关的病毒，感染超过90%的成人。遗憾的是，许多EBV驱动的恶性肿瘤（包括多种B细胞淋巴瘤）侵袭性强，且缺乏可接受的治疗结局。肿瘤微环境中细胞外嘌呤（即ATP和腺苷）浓度高度失调，显著影响针对肿瘤的免疫反应程度。此外，许多肿瘤细胞通过过表达一种或多种胞外核苷酸酶适应这种失调；此类酶可将细胞外核苷酸降解为核苷。胞外核苷酸酶活性将免疫刺激性胞外ATP降解为免疫抑制性腺苷，是肿瘤细胞利用嘌呤能信号通路的一个例子。因此，靶向嘌呤能信号通路的临床前研究已显示其作为实体瘤免疫疗法靶点的前景；然而，嘌呤能信号对EBV⁺ B细胞淋巴瘤发生和生存的影响尚未研究。本研究证明，多种EBV阳性B细胞非霍奇金淋巴瘤（NHL）中胞外核苷酸酶表达强。高浓度胞外ATP可诱导裂解性病毒蛋白表达，并对EBV⁺ B细胞系产生细胞毒性；抑制CD39时效果尤为明显。抑制CD39还显著延长了侵袭性脐带血人源化EBV淋巴瘤小鼠模型的生存期，并与炎症性免疫反应增强和肿瘤负荷降低相关。综上，这些数据提示EBV⁺ B细胞淋巴瘤利用胞外核苷酸酶活性规避ATP介导的炎症和细胞死亡。重要性：EBV是一种普遍存在的病原体，导致全球大量淋巴瘤负担，包括霍奇金淋巴瘤、多种非霍奇金B、T和NK细胞淋巴瘤及淋巴增殖性疾病。EBV还与上皮癌和多发性硬化等自身免疫性疾病相关。许多此类疾病侵袭性强且结局不佳。因此，EBV驱动癌症的新疗法有望惠及大量患者。我们利用体内外模型证明，在EBV驱动的B细胞淋巴瘤背景下，靶向嘌呤能信号通路具有治疗潜力。这些发现支持将嘌呤能信号调控作为治疗EBV⁺恶性肿瘤的可行方法，并支持病毒性淋巴瘤免疫治疗的可行性。
Epstein-Barr virus (EBV) is a cancer-associated virus that infects more than 90% of adults. Unfortunately, many EBV-driven malignancies, including numerous B cell lymphomas, are highly aggressive and lack acceptable therapeutic outcomes. The concentrations of extracellular purines, namely, ATP and adenosine, are highly dysregulated in the tumor microenvironment and significantly impact the degree of immune responses to the tumor. Additionally, many tumor cells adapt to this dysregulation by overexpressing one or more ectonucleotidases, enzymes that degrade extracellular nucleotides to nucleosides. The degradation of immunostimulatory extracellular ATP to immunosuppressive adenosine through ectonucleotidase activity is one example of tumor cell exploitation of the purinergic signaling pathway. As such, preclinical studies targeting the purinergic signaling pathway have found it to be a promising immunotherapeutic target for the treatment of solid tumors; however, the extent to which purinergic signaling impacts the development and survival of EBV + B cell lymphoma remains unstudied. Here, we demonstrate robust ectonucleotidase expression on multiple types of EBV-positive B cell non-Hodgkin lymphoma (NHL). Furthermore, the presence of high concentrations of extracellular ATP resulted in the expression of lytic viral proteins and exhibited cytotoxicity toward EBV + B cell lines, particularly when CD39 was inhibited. Inhibition of CD39 also significantly prolonged survival in an aggressive cord blood humanized mouse model of EBV-driven lymphomagenesis and was correlated with an enhanced inflammatory immune response and reduced tumor burden. Taken together, these data suggest that EBV + B cell lymphomas exploit ectonucleotidase activity to circumvent ATP-mediated inflammation and cell death. IMPORTANCE EBV is a ubiquitous pathogen responsible for significant global lymphoma burden, including Hodgkin lymphoma, numerous non-Hodgkin B, T, and NK cell lymphomas, and lymphoproliferative disorders. EBV is also associated with epithelial cancers and autoimmune diseases, such as multiple sclerosis. Many of these diseases are highly aggressive and exhibit poor outcomes. As such, new treatments for EBV-driven cancers have the potential to benefit a large number of patients. We use in vitro and in vivo models to demonstrate the therapeutic potential of targeting the purinergic signaling pathway in the context of EBV-driven B cell lymphoma. These findings lend credence to the manipulation of purinergic signaling as a viable therapeutic approach to EBV + malignancies and support the feasibility of immunotherapeutic treatments for viral lymphoma.
MEMBER ACCOUNT
登录成功会直接打开下一页。
