Deciphering MDSC function for GBM targeting

解密 GBM 靶向的 MDSC 功能

基本信息

批准号：
10457875
负责人：
Justin D. Lathia
金额：
$ 21.75万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457875
关键词：
Advanced Malignant Neoplasm Agonist Antitumor Response Attenuated Blocking Antibodies Blood - brain barrier anatomy Bone Marrow Cell Communication Cell physiology Cells Clinical Clinical Trials Coculture Techniques Cytotoxic T-Lymphocytes Data Development Failure Generations Genetic Models Glioblastoma Glioma Goals Growth IL8RB gene Immune Immune checkpoint inhibitor Immune response Immune system Immunosuppression Impairment In Vitro Individual Investigation Knockout Mice Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mediating Microglia Modeling Molecular Multiple Sclerosis Myeloid-derived suppressor cells Natural Killer Cells OX40 Pathway interactions Patients Pattern Penetration Peripheral Pharmacology Population Population Heterogeneity Pre-Clinical Model Primary Brain Neoplasms Receptor Activation Receptor Inhibition Refractory Role Signal Transduction Solid Source Spleen System T-Lymphocyte Testing Therapeutic Translating Treatment Efficacy Tumor Escape Tumor Immunity Tumor-infiltrating immune cells anti-cancer anti-tumor immune response base cancer stem cell cell type checkpoint inhibition clinical development clinically relevant differential expression disease prognosis effective therapy genetic signature granulocyte immune activation immune cell checkpoints improved in vivo inhibitor mRNA Differential Displays macrophage melanoma migration monocyte neoplastic cell patient prognosis peripheral blood pre-clinical receptor receptor function response self-renewal success therapy outcome translational goal tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

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.

抽象的尽管潜在抗肿瘤免疫细胞大量积累，胶质母细胞瘤（GBM）仍维持其生长通过建立免疫抑制微环境来促进和进展。多个领域的主要临床工作晚期癌症通过免疫检查点抑制来激活 T 细胞。这些策略是基于其他方面的成功，目前正在对 GBM（最常见的原发性恶性脑癌）进行评估癌症。然而，这些方法并非都取得成功，可能是由于大量的对抗 T 细胞激活疗法的免疫抑制机制。骨髓源性抑制细胞 (MDSC) 是一种异质的免疫抑制细胞群，在肿瘤中积累，对免疫检查点抑制剂耐药的患者中升高。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，其中 M- 和 G-MDSC 表现出不同的肿瘤渗透性，并且与患者预后较差。 MDSC 对肿瘤细胞产生的信号作出反应，包括分泌巨噬细胞迁移抑制因子 (MIF)，M- 和 G-MDSC 均表达 MIF 受体，尽管不同的图案。这些肿瘤细胞-MDSC 相互作用导致有效的免疫抑制，并靶向缓解这种免疫抑制的 MDSC 在临床前 GBM 模型中具有生存优势。给定由于该肿瘤中存在大量免疫抑制性 MDSC，因此单独激活 T 细胞可能无法足以减弱肿瘤生长。然而，可能有机会产生持久的免疫通过同时激活 T 细胞并结合抑制 MDSC 来产生反应。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利用的具体信号机制，包括 MIF 轴。第二个翻译目标是确定靶向 MIF 信号轴以减弱 MDSC 功能的结果 T 细胞激活策略可增强免疫激活，从而减少肿瘤生长。根据我们的调查结果和新的初步数据，我们假设 MDSC 子集对 MIF 信号的响应不同，从而导致 GBM 生长期间的差异功能。我们还假设通过 MIF 靶向 MDSC 将降低免疫抑制和增强免疫激活策略的功效。使用新开发的体外共培养体系联合MIF通路敲除小鼠及血脑屏障穿透临床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。目标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。目标 2 将检验以下假设：MIF 受体抑制会减弱 MDSC 功能，并可与免疫激活策略相结合，以减少 GBM 生长。这该项目的长期目标是针对 MDSC 抑制免疫系统的机制与 T 细胞激活策略相结合，产生针对 GBM 的更完整的免疫反应。