Deciphering MDSC function for GBM targeting

摘要 尽管有大量潜在的抗肿瘤免疫细胞的积累，胶质母细胞瘤（GBM）维持其生长 并通过建立免疫抑制微环境来促进疾病进展。在多个领域的主要临床工作 晚期癌症倾向于通过免疫检查点抑制激活T细胞。这些策略 目前正在评估GBM，最常见的原发性恶性脑癌，基于其他癌症的成功， 癌的然而，这些方法并没有取得一致的成功，可能是由于大量的 免疫抑制机制抵消T细胞活化疗法。髓源性抑制细胞 （MDSC）是在肿瘤中积累的免疫抑制细胞的异质群体， 在免疫检查点抑制剂难治性患者中升高。单核细胞（M-）和粒细胞（G-）MDSC 亚群具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-和G-MDSC显示差异肿瘤渗透，并且与 病人预后很差MDSC响应肿瘤细胞产生的信号，包括分泌 巨噬细胞迁移抑制因子（MIF），M-和G-MDSC表达MIF受体，尽管在 不同的模式。这些肿瘤细胞-MDSC相互作用导致有效的免疫抑制和靶向， MDSC缓解这种免疫抑制在临床前GBM模型中赋予存活优势。给定 在这种肿瘤中存在大量的免疫抑制性MDSC，单独的活化T细胞可能不被 足以减弱肿瘤生长。然而，可能有机会产生持久的免疫力 这通过同时活化T细胞与抑制MDSC的组合来实现。 该项目的第一个转化目标是评估M-和G-MDSC对GBM生长的个体功能 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信号传导轴以减弱MDSC功能的结果， T细胞激活策略，以增强免疫激活，减少肿瘤生长。根据我们的发现， 新的初步数据，我们假设MDSC子集对MIF信号的反应不同，导致 GBM生长过程中的差异功能。我们还假设通过MIF靶向MDSC将降低免疫应答。 抑制和增强免疫激活策略的功效。使用新开发的体外共- 一种结合MIF通路敲除小鼠和临床穿透血脑屏障的培养体系 相关抑制剂和临床前模型，我们将通过以下具体目标来检验这一假设。要求1 将检验MDSC亚型通过不同的MIF信号传导差异调节GBM生长的假设 反应和免疫抑制能力。目的2将检验MIF受体抑制将 减弱MDSC功能，并且可以与免疫激活策略组合以减少GBM生长。的 该项目的长期目标是针对MDSC抑制免疫系统的机制 与T细胞活化策略组合以产生针对GBM的更完全的免疫应答。

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.