巨噬细胞极化通过联合免疫病毒疗法和免疫检查点阻断促进胶质母细胞瘤的根除。
Macrophage Polarization Contributes to Glioblastoma Eradication by Combination Immunovirotherapy and Immune Checkpoint Blockade.
作者信息
Saha Dipongkor, Martuza Robert L, Rabkin Samuel D
机构信息
Molecular Neurosurgery Laboratory and the Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA; Department of Neurosurgery, Harvard Medical School, Boston, MA, USA.
Molecular Neurosurgery Laboratory and the Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA; Department of Neurosurgery, Harvard Medical School, Boston, MA, USA.
出版信息
Cancer Cell. 2017 Aug 14;32(2):253-267.e5. doi: 10.1016/j.ccell.2017.07.006.
Abstract
Glioblastoma is an immunosuppressive, fatal brain cancer that contains glioblastoma stem-like cells (GSCs). Oncolytic herpes simplex virus (oHSV) selectively replicates in cancer cells while inducing anti-tumor immunity. oHSV G47Δ expressing murine IL-12 (G47Δ-mIL12), antibodies to immune checkpoints (CTLA-4, PD-1, PD-L1), or dual combinations modestly extended survival of a mouse glioma model. However, the triple combination of anti-CTLA-4, anti-PD-1, and G47Δ-mIL12 cured most mice in two glioma models. This treatment was associated with macrophage influx and M1-like polarization, along with increased T effector to T regulatory cell ratios. Immune cell depletion studies demonstrated that CD4 and CD8 T cells as well as macrophages are required for synergistic curative activity. This combination should be translatable to the clinic and other immunosuppressive cancers.
摘要
胶质母细胞瘤是一种具有免疫抑制性的致命性脑癌，其中含有胶质母细胞瘤干细胞样细胞（GSCs）。溶瘤单纯疱疹病毒（oHSV）在癌细胞中选择性复制，同时诱导抗肿瘤免疫。表达小鼠白细胞介素-12的oHSV G47Δ（G47Δ-mIL12）、免疫检查点抗体（CTLA-4、PD-1、PD-L1）或双重组合可适度延长小鼠胶质瘤模型的生存期。然而，抗CTLA-4、抗PD-1和G47Δ-mIL12的三联组合治愈了两个胶质瘤模型中的大多数小鼠。这种治疗与巨噬细胞流入和M1样极化有关，同时T效应细胞与T调节细胞的比例增加。免疫细胞耗竭研究表明，协同治愈活性需要CD4和CD8 T细胞以及巨噬细胞。这种联合治疗应该可以转化到临床以及其他免疫抑制性癌症的治疗中。
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