Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors.
Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors.
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DOI：
10.1158/1078-0432.ccr-14-0514
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发表时间：
2014-10-15
期刊：
影响因子：
--
通讯作者：
Lesniak MS
中科院分区：
文献类型：
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作者：
Wainwright DA;Chang AL;Dey M;Balyasnikova IV;Kim CK;Tobias A;Cheng Y;Kim JW;Qiao J;Zhang L;Han Y;Lesniak MS
胶质母细胞瘤（GBM）是成人最常见的恶性胶质瘤。尽管受到血脑屏障和血肿瘤屏障的保护，T 细胞仍积极浸润 GBM。先前的研究表明，IDO、CTLA-4 和 PD-L1 是抑制 GBM 免疫的主要分子参与者。这包括 IDO 介导的调节性 T 细胞（Treg；CD4+CD25+FoxP3+）积累、T 细胞表达的 CTLA-4 与树突状细胞表达的 CD80 的相互作用，以及肿瘤和/或巨噬细胞表达的 PD-L1 与 T 细胞表达的 PD-1 的相互作用。在实验性 GBM 中，每条通路的单独抑制已被证明可以提高存活率。然而，由于同时靶向血液肿瘤屏障中所有三种途径的影响，GBM 被 T 细胞积极浸润。在本报告中，我们证明，当受到双重攻击时，IDO 缺陷型肿瘤相对于具有 IDO 能力的肿瘤具有选择性竞争性生存优势。接下来，我们提供了关于色氨酸分解代谢酶表达的新观察结果，随后表明，在已建立的胶质瘤小鼠模型中治疗性抑制 IDO、CTLA-4 和 PD-L1 可最大程度地减少肿瘤浸润 Tregs，与 T 细胞介导的长期存活率显着增加相一致。事实上，经过三重联合治疗后，100% 患有颅内肿瘤的小鼠都能长期存活。 T 细胞表达的 CD44、CTLA-4、PD-1 和 IFN-γ 的表达和/或频率取决于免疫治疗施用后的时间。总的来说，这些数据提供了强有力的临床前证据，表明恶性胶质瘤的组合靶向免疫抑制是一种对 GBM 患者的未来临床试验具有很高潜在价值的策略。
Glioblastoma (GBM) is the most common form of malignant glioma in adults. Although protected by both the blood brain- and blood tumor-barriers, T cells actively infiltrate GBM. Previous work has shown that IDO, CTLA-4 and PD-L1 are dominant molecular participants in the suppression of GBM immunity. This includes IDO-mediated regulatory T cell (Treg; CD4+CD25+FoxP3+) accumulation, the interaction of T cell-expressed, CTLA-4, with dendritic cell-expressed, CD80, as well as the interaction of tumor- and/or macrophage-expressed, PD-L1, with T cell-expressed, PD-1. The individual inhibition of each pathway has been shown to increase survival in the context of experimental GBM. However, the impact of simultaneously targeting all three pathways in blood tumor-barriers, GBMs are actively infiltrated by T cells. In this report, we demonstrate that, when dually-challenged, IDO-deficient tumors provide a selectively competitive survival advantage against IDO-competent tumors. Next, we provide novel observations regarding tryptophan catabolic enzyme expression, before showing that the therapeutic inhibition of IDO, CTLA-4 and PD-L1 in a mouse model of well-established glioma maximally decreases tumor-infiltrating Tregs, coincident with a significant increase in T cell-mediated long-term survival. In fact, 100% of mice bearing intracranial tumors were long-term survivors following triple combination therapy. The expression and/or frequency of T cell-expressed CD44, CTLA-4, PD-1 and IFN-γ depended on timing after immunotherapeutic administration. Collectively, these data provide strong pre-clinical evidence that combinatorially-targeting immunosuppression in malignant glioma is a strategy that has high potential value for future clinical trials in patients with GBM.