Nair Sharmila, Mazzoccoli Luciano, Jash Arijita, Govero Jennifer, Bais Sachendra S, Hu Tong, Fontes-Garfias Camila R, Shan Chao, Okada Hideho, Shresta Sujan, Rich Jeremy N, Shi Pei-Yong, Diamond Michael S, Chheda Milan G
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
JCI Insight. 2021 Jan 11;6(1):144619. doi: 10.1172/jci.insight.144619.
Glioblastoma multiforme (GBM) is a fatal human cancer in part because GBM stem cells are resistant to therapy and recurrence is inevitable. Previously, we demonstrated Zika virus (ZIKV) targets GBM stem cells and prevents death of mice with gliomas. Here, we evaluated the immunological basis of ZIKV-mediated protection against GBM. Introduction of ZIKV into the brain tumor increased recruitment of CD8+ T and myeloid cells to the tumor microenvironment. CD8+ T cells were required for ZIKV-dependent tumor clearance because survival benefits were lost with CD8+ T cell depletion. Moreover, while anti-PD-1 antibody monotherapy moderately improved tumor survival, when coadministered with ZIKV, survival increased. ZIKV-mediated tumor clearance also resulted in durable protection against syngeneic tumor rechallenge, which also depended on CD8+ T cells. To address safety concerns, we generated an immune-sensitized ZIKV strain, which was effective alone or in combination with immunotherapy. Thus, oncolytic ZIKV treatment can be leveraged by immunotherapies, which may prompt combination treatment paradigms for adult patients with GBM.
多形性胶质母细胞瘤（GBM）是一种致命的人类癌症，部分原因是GBM干细胞对治疗有抗性且复发不可避免。此前，我们证明寨卡病毒（ZIKV）靶向GBM干细胞并可防止患有胶质瘤的小鼠死亡。在此，我们评估了ZIKV介导的针对GBM的保护作用的免疫学基础。将ZIKV引入脑肿瘤会增加CD8 + T细胞和髓样细胞向肿瘤微环境的募集。CD8 + T细胞是ZIKV依赖的肿瘤清除所必需的，因为去除CD8 + T细胞后生存益处消失。此外，虽然抗PD-1抗体单一疗法适度改善了肿瘤生存，但与ZIKV联合使用时，生存率提高。ZIKV介导的肿瘤清除还导致对同基因肿瘤再次攻击产生持久保护，这也依赖于CD8 + T细胞。为了解决安全性问题，我们构建了一种免疫致敏的ZIKV毒株，其单独使用或与免疫疗法联合使用均有效。因此，溶瘤性ZIKV治疗可与免疫疗法联合使用，这可能促使为成年GBM患者采用联合治疗模式。
