Immunosuppressive Myeloid Cells' Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy
Immunosuppressive Myeloid Cells' Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy
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DOI：
10.1016/j.ymthe.2016.10.003
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发表时间：
2017-01-04
影响因子：
12.4
通讯作者：
Castro, Maria G.
中科院分区：
文献类型：
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作者：
Kamran, Neha;Kadiyala, Padma;Castro, Maria G.
接受当前标准治疗的胶质瘤（胶质母细胞瘤，GBM）患者的生存率仍然很低。利用宿主免疫系统的细胞毒性和记忆潜能的免疫治疗方法在其他癌症中已显示出巨大益处。胶质母细胞瘤已发展出多种策略，包括髓源性抑制细胞（MDSCs）的积聚来诱导免疫抑制。因此，在旨在产生强大的抗肿瘤免疫反应时，开发多管齐下的方法是至关重要的。在此，我们测试了联合MDSC耗竭或检查点阻断是否会增强免疫刺激性单纯疱疹病毒I型胸苷激酶（TK）加上Fms样酪氨酸激酶配体（Flt3L）介导的免疫刺激基因治疗的疗效。我们的结果显示，MDSCs占肿瘤浸润免疫细胞的40%以上。这些细胞表达白细胞介素 - 4受体α（IL - 4Rα）、诱导型一氧化氮合酶（iNOS）、精氨酸酶、程序性死亡配体1（PDL1）和CD80，这些分子在抗原特异性T细胞抑制中起关键作用。MDSCs的耗竭极大地增强了TK/Flt3L基因治疗诱导的肿瘤特异性CD8 T细胞反应，这导致中位生存期延长和长期幸存者的百分比增加。此外，联合程序性死亡配体1（PDL1）或细胞毒性T淋巴细胞相关抗原4（CTLA - 4）免疫检查点阻断极大地提高了TK/Flt3L基因治疗的疗效。因此，我们的结果表明，阻断MDSC介导的免疫抑制对于提高基因治疗介导的胶质母细胞瘤免疫疗法的疗效具有很大的前景。
Survival of glioma (GBM) patients treated with the current standard of care remains dismal. Immunotherapeutic approaches that harness the cytotoxic and memory potential of the host immune system have shown great benefit in other cancers. GBMs have developed multiple strategies, including the accumulation of myeloid-derived suppressor cells (MDSCs) to induce immunosuppression. It is therefore imperative to develop multipronged approaches when aiming to generate a robust anti-tumor immune response. Herein, we tested whether combining MDSC depletion or checkpoint blockade would augment the efficacy of immune-stimulatory herpes simplex type-I thymidine kinase (TK) plus Fms-like tyrosine kinase ligand (F1t3L)-mediated immune stimulatory gene therapy. Our results show that MDSCs constitute >40% of the tumor-infiltrating immune cells. These cells express IL-4R alpha, inducible nitric oxide synthase (iNOS), arginase, programmed death ligand 1 (PDL1), and CD80, molecules that are critically involved in antigen-specific T cell suppression. Depletion of MDSCs strongly enhanced the TK/Flt3L gene therapy-induced tumor-specific CD8 T cell response, which lead to increased median survival and percentage of long-term survivors. Also, combining PDL1 or CTLA-4 immune checkpoint blockade greatly improved the efficacy of TK/Flt3L gene therapy. Our results, therefore, indicate that blocking MDSC-mediated immunosuppression holds great promise for increasing the efficacy of gene therapy-mediated immunotherapies for GBM.