Oncolytic Virus Therapy with HSV-1 for Hematological Malignancies
Oncolytic Virus Therapy with HSV-1 for Hematological Malignancies
复制标题
DOI：
10.1016/j.ymthe.2020.09.041
复制
发表时间：
2021-02-03
影响因子：
12.4
通讯作者：
Kadowaki, Norimitsu
中科院分区：
文献类型：
--
作者：
Ishino, Ryo;Kawase, Yumi;Kadowaki, Norimitsu
溶瘤性单纯疱疹病毒1型（HSV-1）已被研究，以扩大其应用于各种恶性肿瘤。由于造血细胞对HSV-1具有抗性，因此其在血液恶性肿瘤中的应用很少。在这里，我们发现第三代溶瘤性HSV-1（T-01）感染并杀死了26种人类细胞系中的18种和来自各种血液恶性肿瘤谱系的15种原代细胞中的8种。T-01在细胞系中以低水平复制。病毒进入和溶瘤作用与nectin-1的表达水平呈正相关，并且在较小程度上与HSV-1的糖蛋白D的受体3-O-硫酸化硫酸乙酰肝素在肿瘤细胞上的表达水平呈正相关。将nectin-1转染到nectin-1阴性肿瘤细胞中使其对T-01敏感。溶瘤作用似乎与干扰素基因（STING）和PKR-eIF 2 α通路的环GMP-AMP（cGAS）-刺激因子中抗病毒分子的表达或磷酸化无关。在免疫活性小鼠模型中，肿瘤内注射T-01至淋巴瘤诱导了注射的以及未注射的对侧肿瘤的消退，伴随着抗原特异性CD 8（+）T细胞的大量浸润。这些数据表明，瘤内注射溶瘤HSV-1可能适用于系统性血液恶性肿瘤。Nectin-1表达可能是最佳疗效的最有用的生物标志物。
Oncolytic herpes simplex virus type 1 (HSV-1) has been investigated to expand its application to various malignancies. Because hematopoietic cells are resistant to HSV-1, its application to hematological malignancies has been rare. Here, we show that the third generation oncolytic HSV-1, T-01, infected and killed 18 of 26 human cell lines and 8 of 15 primary cells derived from various lineages of hematological malignancies. T-01 replicated at low levels in the cell lines. Viral entry and the oncolytic effect were positively correlated with the expression level of nectin-1 and to a lesser extent 3-O-sulfated heparan sulfate, receptors for glycoprotein D of HSV-1, on tumor cells. Transfection of nectin-1 into nectin-1-negative tumor cells made them susceptible to T-01. The oncolytic effects did not appear to correlate with the expression or phosphorylation of antiviral molecules in the cyclic GMP-AMP (cGAS)-stimulator of interferon genes (STING) and PKR-eIF2 alpha pathways. In an immunocompetent mouse model, intratumoral injection of T-01 into lymphoma induced regression of injected, as well as non-injected, contralateral tumors accompanied by abundant infiltration of antigen-specific CD8(+) T cells. These data suggest that intratumoral injection of oncolytic HSV-1 may be applicable to systemic hematological malignancies. Nectin-1 expression may be the most useful biomarker for optimal efficacy.