Tumor Resection Recruits Effector T Cells and Boosts Therapeutic Efficacy of Encapsulated Stem Cells Expressing IFNβ in Glioblastomas.
Tumor Resection Recruits Effector T Cells and Boosts Therapeutic Efficacy of Encapsulated Stem Cells Expressing IFNβ in Glioblastomas.
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DOI：
10.1158/1078-0432.ccr-17-0077
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发表时间：
2017-11-15
期刊：
影响因子：
--
通讯作者：
Shah K
中科院分区：
文献类型：
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作者：
Choi SH;Stuckey DW;Pignatta S;Reinshagen C;Khalsa JK;Roozendaal N;Martinez-Quintanilla J;Tamura K;Keles E;Shah K
尽管肿瘤切除是胶质母细胞瘤（GBM）患者的一线临床护理，但几乎所有的临床前免疫治疗模型都旨在治疗已建立的GBM肿瘤。细胞减少手术诱导的免疫反应特征与免疫细胞因子的施用相结合，有可能为GBMs提供新的免疫治疗范例。我们建立了肿瘤切除的同基因原位小鼠GBM模型，并描述了完整和切除肿瘤的免疫反应。我们还创建了一种高分泌型的免疫细胞因子IFNβ，以增强其从工程小鼠间充质干细胞（MSC-IFNβ）中的释放，并评估了手术切除颅内GBM肿瘤是否显著增强靶向现场递送包封的MSC-IFNβ的抗肿瘤功效。我们发现，肿瘤减体积导致髓源性抑制细胞（MDSCs）的大量减少和CD4/CD8 T细胞的同时募集。这种免疫反应显著增强了局部递送的msc - ifn β的抗肿瘤效果。IFNβ增强手术后CD8 T细胞的选择性浸润，并直接诱导肿瘤细胞的细胞周期阻滞，从而提高小鼠的存活率。利用包封的msc -IFNβ在切除的患者源性GBM原位肿瘤异种移植物中，我们进一步表明，IFNβ诱导细胞周期阻滞，随后凋亡，导致免疫受损小鼠的存活增加，尽管它们缺乏完整的免疫系统。本研究证明了同基因肿瘤切除模型在发展癌症免疫治疗中的重要性，并强调了局部递送免疫治疗剂治疗癌症的转化潜力。
Despite tumor resection being the frontline clinical care for glioblastoma (GBM) patients, nearly all preclinical immune therapy models intends to treat established GBM tumor. Characterizing cytoreductive surgery-induced immune-response combined with the administration of immune cytokines has the potential of offering a new treatment paradigm of immune therapy for GBMs. We developed syngeneic orthotopic mouse GBM models of tumor-resection and characterized the immune response of intact and resected tumors. We also created a highly secretable variant of immune cytokine IFNβ to enhance the its release from engineered mouse mesenchymal stem cells (MSC-IFNβ) and assessed whether surgical resection of intracranial GBM tumor significantly enhance the anti-tumor efficacy of targeted on-site delivery of encapsulated-MSC-IFNβ. We show that tumor debulking results in substantial reduction of myeloid-derived suppressor cells (MDSCs) and simultaneous recruitment of CD4/CD8 T cells. This immune response significantly enhanced the anti-tumor efficacy of locally delivered encapsulated-MSC-IFNβ. IFNβ enhanced selective post-surgical infiltration of CD8 T cells and directly induced cell-cycle arrest in tumor cells resulting in increased survival of mice. Utilizing encapsulated-MSC-IFNβ in resected orthotopic tumor xenografts of patient-derived GBM, we further show that IFNβ induces cell-cycle arrest followed by apoptosis resulting in increased survival in immune-compromised mice despite their absence of an intact immune system. This study demonstrates the importance of syngeneic tumor resection models in developing cancer immunotherapies and emphasizes the translational potential of local delivery of immune-therapeutic agents in treating cancer.