Radiation with STAT3 Blockade Triggers Dendritic Cell-T cell Interactions in the Glioma Microenvironment and Therapeutic Efficacy.
Radiation with STAT3 Blockade Triggers Dendritic Cell-T cell Interactions in the Glioma Microenvironment and Therapeutic Efficacy.
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DOI：
10.1158/1078-0432.ccr-19-4092
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发表时间：
2020-09-15
影响因子：
11.5
通讯作者：
Heimberger, Amy B.
中科院分区：
文献类型：
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作者：
Ott, Martina;Kassab, Cynthia;Marisetty, Anantha;Hashimoto, Yuuri;Wei, Jun;Zamler, Daniel;Leu, Jia-Shiun;Tomaszowski, Karl-Heinz;Sabbagh, Aria;Fang, Dexing;Gupta, Pravesh;Priebe, Waldemar;Zielinski, Rafal J.;Burks, Jared K.;Long, James P.;Kong, Ling-Yuan;Fuller, Gregory N.;DeGroot, John;Sulman, Erik P.;Heimberger, Amy B.
中枢神经系统(CNS)肿瘤患者通常接受放射治疗，但放射治疗无法治愈，并导致磷酸化信号转导和转录激活因子3(p-STAT3)上调，从而推动侵袭、血管生成和免疫抑制。因此，我们研究了STAT3抑制剂和全脑放射治疗(WBRT)在小鼠脑胶质瘤模型中的联合作用。C57BL/6小鼠接受了GL261胶质瘤细胞脑内移植、WBRT和WP1066治疗，WP1066是一种血脑屏障(BBB)穿透性STAT3途径抑制剂，或两者联合治疗。免疫系统的作用通过肿瘤再攻击策略、免疫失能背景、免疫荧光、肿瘤浸润性免疫细胞的免疫表型(通过流式细胞术)和来自免疫细胞的770个免疫相关基因的纳米串基因表达分析来评估，包括那些直接从肿瘤微环境中分离的基因。在GL261胶质瘤模型中，WP1066和WBRT的联合治疗导致长期存活期和中位生存时间相对于单一治疗的延长(联合治疗与对照组P<；0.0001)。免疫记忆似乎被诱导了，因为小鼠在随后的肿瘤再攻击中受到了保护。在免疫功能低下的动物身上，这种联合疗法的治疗效果完全丧失。纳米线分析和免疫荧光显示，中枢神经系统肿瘤微环境中的免疫重编特别影响树突状细胞抗原提呈和T细胞效应器功能。本研究表明，STAT3抑制剂联合WBRT可通过诱导中枢神经系统肿瘤中树突状细胞和T细胞的相互作用来增强对中枢神经系统胶质瘤的治疗效果。考虑到胶质瘤的异质性，单一的治疗策略不太可能在患者中引起持久的反应。这项研究结合了标准护理放射治疗和血脑屏障渗透性小分子抑制剂WP1066，WP1066可以阻断目前处于临床试验中的信号转导和转录激活因子3(STAT3)的转录活性(NCT01904123)。放射和WP1066的组合在临床前胶质瘤小鼠模型中显示出显著的治疗反应，这是由免疫系统介导的，因为治疗效果在免疫功能不全的模型中消失。通过使用CNS和外周免疫区段的纳米串图谱和免疫荧光，我们发现WP1066和辐射的结合在胶质瘤微环境中诱导树突状细胞-T细胞相互作用，这似乎是全功能免疫反应的必要条件。这些数据为脑胶质瘤患者的临床试验考虑提供了强有力的依据。
Patients with central nervous system (CNS) tumors are typically treated with radiation therapy, but this is not curative and results in the upregulation of phosphorylated signal transducer and activator of transcription 3 (p-STAT3), which drives invasion, angiogenesis, and immune suppression. Therefore, we investigated the combined effect of an inhibitor of STAT3 and whole-brain radiation therapy (WBRT) in a murine model of glioma. C57BL/6 mice underwent intracerebral implantation of GL261 glioma cells, WBRT, and treatment with WP1066, a blood-brain barrier (BBB)-penetrant inhibitor of the STAT3 pathway, or the two in combination. The role of the immune system was evaluated using tumor rechallenge strategies, immune incompetent backgrounds, immunofluorescence, immune phenotyping of tumor-infiltrating immune cells (via flow cytometry), and nanostring gene expression analysis of 770 immune-related genes from immune cells, including those directly isolated from the tumor microenvironment. The combination of WP1066 and WBRT resulted in long-term survivors and enhanced median survival time relative to monotherapy in the GL261 glioma model (combination vs. control p<0.0001). Immunological memory appeared to be induced, because mice were protected during subsequent tumor rechallenge. The therapeutic effect of the combination was completely lost in immune incompetent animals. Nanostring analysis and immunofluorescence revealed immunological reprograming in the CNS tumor microenvironment specifically affecting dendritic-cell antigen presentation and T cell effector functions. This study indicates that the combination of STAT3 inhibition and WBRT enhances the therapeutic effect against gliomas in the CNS by inducing dendritic-cell and T cell interactions in the CNS tumor. Given the heterogeneous nature of gliomas, it is unlikely that a monotherapeutic strategy would induce durable responses across patients. This study combines standard-of-care radiation therapy and a BBB-penetrant small molecule inhibitor, WP1066, which blocks the transcriptional activity of the signal transducer and activator of transcription 3 (STAT3), which is currently in clinical trials (NCT01904123). The combination of radiation and WP1066 demonstrated a marked therapeutic response in a preclinical glioma mouse model, which was mediated by the immune system, because since the therapeutic effect is lost in immune-incompetent models. By using nanostring profiling from both the CNS and the peripheral immune compartments and immunofluorescence, we found that the combination of WP1066 and radiation induces dendritic cell-T cell interactions in the glioma microenvironment, which seems to be a requirement for a fully functional immune response. These data provide a strong rationale for clinical trial consideration in glioma patients.