Combination viroimmunotherapy with checkpoint inhibition to treat glioma, based on location-specific tumor profiling
Combination viroimmunotherapy with checkpoint inhibition to treat glioma, based on location-specific tumor profiling
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DOI：
10.1093/neuonc/nov173
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发表时间：
2016-04-01
期刊：
影响因子：
15.9
通讯作者：
Vile, Richard
中科院分区：
文献类型：
--
作者：
Cockle, Julia V.;Rajani, Karishma;Vile, Richard
背景从水泡性口炎病毒（VSV）表达的互补cDNA文库的全身递送通过针对广泛的肿瘤相关抗原（TAA）接种疫苗来治疗肿瘤。对于皮下B16黑色素瘤，使用VSV表达的自身TAA（神经母细胞瘤-Ras，细胞色素c和酪氨酸酶相关蛋白1）的特定组合进行治疗。然而，对于颅内B16肿瘤，不同的组合是治疗性的（由VSV表达的缺氧诱导因子[HIF]-2 α、Sox-10、c-Myc和酪氨酸酶相关蛋白1组成）。因此，我们测试了以下假设：在脑中生长的不同组织学类型的肿瘤共享可用于免疫治疗的共同免疫原性特征。对免疫活性小鼠脑内的同源肿瘤（包括GL 261胶质瘤）进行抗原谱分析或进行系统性病毒免疫治疗。颅内生长的几种不同组织学类型的肿瘤，以及新鲜切除的人脑肿瘤外植体，表达由脑源性CD 11b+细胞施加的HIF-2 α（Hi）表型。使用表达HIF-2 α、Sox-10和c-Myc的全身递送的VSV，在治疗上利用这种位置特异性抗原表达来对抗颅内GL261神经胶质瘤。免疫检查点抑制剂增强了病毒免疫治疗，并与抗肿瘤T辅助细胞1型（Th1）干扰素-γ和Th17 T细胞应答的去抑制相关。由于不同类型的肿瘤生长在大脑中的同一位置共享一个位置特异性表型，我们建议，抗原特异性免疫治疗应基于组织学类型特异性肿瘤抗原和位置特异性抗原的表达。我们的研究结果支持VSV-TAA治疗与检查点抑制对侵袭性脑肿瘤的临床应用，并强调了颅内微环境在塑造肿瘤抗原表达的位置特异性谱中的重要性。
Background. Systemic delivery of a complementary cDNA library expressed from the vesicular stomatitis virus (VSV) treats tumors by vaccinating against a wide range of tumor associated antigens (TAAs). For subcutaneous B16 melanomas, therapy was achieved using a specific combination of self-TAAs (neuroblastoma-Ras, cytochrome c, and tyrosinase-related protein 1) expressed from VSV. However, for intracranial B16 tumors, a different combination was therapeutic (consisting of VSV-expressed hypoxia-inducible factor [HIF]-2 alpha, Sox-10, c-Myc, and tyrosinase-related protein 1). Therefore, we tested the hypothesis that tumors of different histological types growing in the brain share a common immunogenic signature which can be exploited for immunotherapy.Methods. Syngeneic tumors, including GL261 gliomas, in the brains of immune competent mice were analyzed for their antigenic profiles or were treated with systemic viroimmunotherapy.Results. Several different histological types of tumors growing intracranially, as well as freshly resected human brain tumor explants, expressed a HIF-2 alpha(Hi) phenotype imposed by brain-derived CD11b+ cells. This location-specific antigen expression was exploited therapeutically against intracranial GL261 gliomas using systemically delivered VSV expressing HIF-2 alpha, Sox-10, and c-Myc. Viroimmunotherapy was enhanced by immune checkpoint inhibitors, associated with the de-repression of antitumor T-helper cell type 1 (Th1) interferon-gamma and Th17 T cell responses.Conclusions. Since different tumor types growing in the same location in the brain share a location-specific phenotype, we suggest that antigen-specific immunotherapies should be based upon expression of both histological type-specific tumor antigens and location-specific antigens. Our findings support clinical application of VSV-TAA therapy with checkpoint inhibition for aggressive brain tumors and highlight the importance of the intracranial microenvironment in sculpting a location-specific profile of tumor antigen expression.