A novel in situ multiplex immunofluorescence panel for the assessment of tumor immunopathology and response to virotherapy in pediatric glioblastoma reveals a role for checkpoint protein inhibition
A novel in situ multiplex immunofluorescence panel for the assessment of tumor immunopathology and response to virotherapy in pediatric glioblastoma reveals a role for checkpoint protein inhibition
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DOI：
10.1080/2162402x.2019.1678921
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发表时间：
2019-10-20
期刊：
影响因子：
7.2
通讯作者：
Friedman, Gregory K.
中科院分区：
文献类型：
--
作者：
Bernstock, Joshua D.;Vicario, Nunzio;Friedman, Gregory K.
溶瘤性单纯疱疹病毒-1免疫疗法为治疗脑肿瘤提供了一种创新的、有针对性的、毒性较低的方法。然而，最大限度地发挥溶瘤病毒治疗的主要障碍是缺乏对输注病毒后中枢神经系统肿瘤/相关微环境中展开的潜在机制的全面了解。我们证明，我们的多重生物标志物筛选平台全面地通知了居住/浸润免疫细胞的地形位置和功能状态的变化，这些变化在儿童1期患者接受HSV G207治疗后的神经病理学中起作用。使用这种方法，我们发现了CD8(+) T细胞的强大浸润，这表明在病毒治疗后免疫反应被激活；然而，检查点蛋白PD-1、PD-L1、CTLA-4和IDO的相应上调揭示了检查点抑制剂的潜在作用。这样的工作可能最终导致对肿瘤控制病理生物学的理解，从而促进新疗法的发展，以产生最佳的反应。
Immunotherapy with oncolytic herpes simplex virus-1 therapy offers an innovative, targeted, less-toxic approach for treating brain tumors. However, a major obstacle in maximizing oncolytic virotherapy is a lack of comprehensive understanding of the underlying mechanisms that unfold in CNS tumors/associated microenvironments after infusion of virus. We demonstrate that our multiplex biomarker screening platform comprehensively informs changes in both topographical location and functional states of resident/infiltrating immune cells that play a role in neuropathology after treatment with HSV G207 in a pediatric Phase 1 patient. Using this approach, we identified robust infiltration of CD8(+) T cells suggesting activation of the immune response following virotherapy; however there was a corresponding upregulation of checkpoint proteins PD-1, PD-L1, CTLA-4, and IDO revealing a potential role for checkpoint inhibitors. Such work may ultimately lead to an understanding of the governing pathobiology of tumors, thereby fostering development of novel therapeutics tailored to produce optimal responses.