Deciphering MDSC function for GBM targeting

摘要 尽管有大量潜在的抗肿瘤免疫细胞积聚，胶质母细胞瘤(GBM)仍维持其生长。 并通过建立免疫抑制微环境来促进进展。在多个方面的主要临床工作 晚期癌症倾向于通过免疫检查点抑制来激活T细胞。这些策略是 目前正在对基底膜进行评估，这是最常见的原发恶性脑癌，基于在其他方面的成功 癌症。然而，这些方法并不是一致成功的，可能是因为有大量的 抵消T细胞激活疗法的免疫抑制机制。髓系来源的抑制细胞 (MDSCs)是一群异质性的免疫抑制细胞，聚集在肿瘤中，并 在对免疫检查点抑制剂无效的患者中升高。单核细胞(M-)和粒细胞(G-)MDSC 亚群有不同的免疫抑制机制。我们观察到这些细胞存在于 GBM微环境，M-MDSCs和G-MDSCs显示不同的肿瘤穿透性，并与 患者预后不佳。MDSCs对肿瘤细胞产生的信号做出反应，包括分泌 巨噬细胞移动抑制因子(MIF)和M-和G-MDSCs都表达MIF受体，尽管在 不同的图案。这些肿瘤细胞-MDSC的相互作用导致了强大的免疫抑制和靶向 缓解这种免疫抑制的MDSCs在临床前的GBM模型中提供了生存优势。vt.给出 在该肿瘤中存在大量的免疫抑制MDSCs，单独激活T细胞可能不是 足以抑制肿瘤生长。然而，可能有机会产生持久的免疫力。 通过同时激活T细胞和抑制MDSCs来应答。 本项目的第一个翻译目标是评估M-MDSC和G-MDSC在GBM生长中的个体功能 以及它们使用的特定信号机制，包括MIF轴。第二个翻译目标是 确定靶向MIF信号轴以削弱MDSC功能的后果 T细胞激活策略，以增强免疫活性，减少肿瘤生长。根据我们的发现和 新的初步数据，我们假设MDSC子集对MIF信号的反应不同，导致 分化功能在GBM生长过程中的作用。我们还假设，通过MIF靶向MDSCs将降低免疫力 抑制和增强免疫激活策略的功效。使用一种新开发的体外联合 MIF途径基因敲除小鼠与血脑屏障联合培养体系的临床应用 相关的抑制剂和临床前模型，我们将通过以下具体目标来验证这一假说。目标1 将测试MDSC亚型通过不同的MIF信号不同地调节GBM生长的假设 反应和免疫抑制能力。Aim 2将测试MIF受体抑制将 减弱MDSC的功能，并可与免疫激活策略相结合，减少GBM的生长。这个 该项目的长期目标是针对MDSCs用于抑制免疫系统的机制。 与T细胞激活策略相结合，产生针对GBM的更完整的免疫反应。

ABSTRACT Despite a large accumulation of potentially anti-tumoral immune cells, glioblastoma (GBM) sustains its growth and progression by establishing an immunosuppressive microenvironment. Major clinical efforts in multiple advanced cancers are aligned toward activating T cells via immune checkpoint inhibition. These strategies are currently being evaluated for GBM, the most common primary malignant brain cancer, based on success in other cancers. However, these approaches have not been uniformly successful, likely due to an abundance of immunosuppressive mechanisms that counteract T cell-activating therapies. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells that accumulate in tumors and are elevated in patients refractory to immune checkpoint inhibitors. Monocytic (M-) and granulocytic (G-) MDSC subsets have different mechanisms of immune suppression. We observed that these cells are present within the GBM microenvironment, with M- and G-MDSCs displaying differential tumor penetration, and are associated with a poor patient prognosis. MDSCs respond to signals generated by tumor cells, including the secretion of macrophage migration inhibitor factor (MIF), and both M- and G-MDSCs express MIF receptors, although in different patterns. These tumor cell-MDSC interactions result in potent immune suppression, and targeting MDSCs to alleviate this immune suppression confers a survival advantage in pre-clinical GBM models. Given the high number of immunosuppressive MDSCs present in this tumor, activating T cells alone may not be sufficient to attenuate tumor growth. However, there may be an opportunity to generate a durable immune response by concurrently activating T cells in combination with inhibiting MDSCs. The first translational goal of this project is to assess the individual function of M- and G-MDSCs on GBM growth and the specific signaling mechanisms they utilize, including the MIF axis. The second translational goal is to determine the consequence of targeting the MIF signaling axis to attenuate MDSC function in conjunction with T cell-activating strategies to enhance immune activation to reduce tumor growth. Based on our findings and new preliminary data, we hypothesize that MDSC subsets respond to MIF signaling differently, resulting in differential function during GBM growth. We also hypothesize that targeting MDSCs via MIF will reduce immune suppression and enhance the efficacy of immune activating strategies. Using a newly developed in vitro co- culture system in combination with MIF pathway knockout mice and blood-brain barrier-penetrating clinically relevant inhibitors and pre-clinical models, we will test this hypothesis through the following specific aims. Aim 1 will test the hypothesis that MDSC subtypes differentially regulate GBM growth via distinct MIF signaling responses and immunosuppressive capacities. Aim 2 will test the hypothesis that MIF receptor inhibition will attenuate MDSC function and can be combined with immune activating strategies to reduce GBM growth. The long-term goal of this project is to target the mechanisms employed by MDSCs to suppress the immune system in combination with T cell-activating strategies to generate a more complete immune response against GBM.