Contribution of Myeloid-Derived Suppressor Cells to Neuro-Inflammatory Alterations and Disease Progression in Glioblastoma

骨髓源性抑制细胞对胶质母细胞瘤神经炎症改变和疾病进展的贡献

• 批准号: 10444016
• 负责人: Justin D. Lathia
• 金额: $ 45.43万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2030-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444016
• 关键词: Address; Advanced Malignant Neoplasm; Area; Biological Markers; Brain; Cell Lineage; Cells; Clinical; Cues; Development; Disease Progression; Epigenetic Process; Funding; Genetic; Glioblastoma; Growth; Immune; Immune checkpoint inhibitor; Immune response; Immunosuppression; Knowledge; Laboratories; Malignant neoplasm of brain; Mediating; Molecular; Myeloid-derived suppressor cells; Nervous system structure; Neurodegenerative Disorders; Neuroimmune system; Neurological Models; Patients; Primary Brain Neoplasms; Prognosis; Series; Signal Transduction; Testing; Therapeutic; Work; cancer stem cell; cytotoxic; flexibility; granulocyte; gut-brain axis; immune activation; insight; microorganism interaction; monocyte; nervous system disorder; neuroinflammation; novel therapeutics; pre-clinical; proctolin; programs; relating to nervous system; response; sex; stem cell function; success; therapeutic target; tumor; tumor growth

ABSTRACT: Glioblastoma (GBM), the most common primary brain tumor, remains uniformly lethal due to many factors, including a potently immune-suppressive microenvironment. While attempts to alter immune activation have been successful in other advanced cancers, a series of diverse strategies has yet to markedly increase GBM patient survival. These results demonstrate a key clinical barrier to success and underscore the need to better understand the immune-suppressive GBM microenvironment, which is part of a unique neuroimmune system. Central to immune suppression in GBM is the presence of myeloid-derived suppressor cells (MDSCs), an immature lineage comprised of monocytic (m) and granulocytic (g) subsets that potently suppresses cytotoxic immune response. Interrogating the function of MDSCs in GBM has been a major focus of our laboratory. Using an integrated approach, we have shown that MDSCs associate with poor GBM prognosis, drive cancer stem cell function, and interact with the tumor through multiple signaling networks that can be neutralized to increase immune activation. We have also interrogated MDSC subsets to reveal differences in localization and function in a sex-specific manner and identified MDSC subset signaling programs that can be altered to increase immune activation and decrease GBM growth. While our work has implicated MDSCs as biomarkers and drivers of GBM progression and identified them as next-generation therapeutic targets, there are several knowledge gaps that remain, and addressing them is the focus of this application: it remains unclear how MDSCs originate and the extent of their plasticity; it is unclear how MDSC lineage commitment is informed by cell-intrinsic programs and is altered as a result of interaction with unique neural microenvironments, microbial interactions, and signaling programs; and the efficacy of targeting MDSC subsets in combination with immune activating strategies has yet to be determined. The overarching hypothesis of this application is that MDSC subset lineage commitment is driven though the integration of cell-intrinsic (including sex-specific genetic and epigenetic programs) and cell- extrinsic (including systemic factors from the gut-brain axis) interactions that can be leveraged for the development of more effective anti-GBM therapies. Through this R35 mechanism that allows for longer- term/flexible funding to develop parallel areas with synergistic potential, we will test distinct aspects of this hypothesis though three complementary but integrated focus areas: (1) the cellular and molecular basis for MDSC lineage commitment and plasticity, (2) the response of MDSCs to microenvironmental cues, and (3) pre- clinical MDSC targeting in combination with immune activating therapies. These studies have immediate implications for GBM and other neurological disorders and establish a platform for understanding immune responses in other neurological disorders by providing unique insights into neural/immune interactions mediated via MDSCs, as well as by assessing brain-penetrant immune-altering therapeutic strategies.

摘要：胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，由于多种原因， 因素，包括一个强大的免疫抑制微环境。虽然试图改变免疫激活 虽然在其他晚期癌症中取得了成功，但一系列不同的策略尚未显着增加 GBM患者生存率。这些结果证明了成功的关键临床障碍，并强调了需要 更好地了解免疫抑制GBM微环境，这是一个独特的神经免疫系统的一部分， 系统GBM中免疫抑制的核心是髓源性抑制细胞（MDSC）的存在， 由单核细胞（m）和粒细胞（g）亚群组成的未成熟谱系，可有效抑制细胞毒性 免疫反应探究MDSC在GBM中的功能一直是我们实验室的主要焦点。使用 作为一种综合方法，我们已经证明MDSC与GBM预后不良相关， 功能，并通过多种信号网络与肿瘤相互作用，这些信号网络可以被中和， 免疫激活我们还询问了MDSC亚群，以揭示其定位和功能的差异 以性别特异性的方式，并确定了可以改变以增加免疫应答的MDSC子集信号程序。 激活并减少GBM生长。虽然我们的工作涉及MDSC作为GBM的生物标志物和驱动因素， 进展并将其确定为下一代治疗靶点，但仍存在一些知识空白， 仍然存在，解决这些问题是本申请的重点：目前还不清楚MDSC是如何起源的， 它们的可塑性程度;目前还不清楚MDSC谱系承诺是如何被细胞内在程序告知的， 由于与独特的神经微环境、微生物相互作用和信号传导的相互作用， 计划;靶向MDSC亚群与免疫激活策略相结合的疗效还没有 有待确定。本申请的首要假设是MDSC子集谱系承诺是 通过整合细胞内在（包括性别特异性遗传和表观遗传程序）和细胞， 外源性（包括来自肠-脑轴的全身性因素）相互作用，可用于 开发更有效的抗GBM疗法。通过这种R35机制，允许更长的时间- 定期/灵活的资金，以发展具有协同潜力的平行领域，我们将测试这方面的不同方面， 假设通过三个互补但综合的重点领域：（1）细胞和分子基础 MDSC谱系定型和可塑性，（2）MDSC对微环境线索的反应，以及（3）前 临床MDSC靶向与免疫活化疗法组合。这些研究直接 GBM和其他神经系统疾病的影响，并建立一个平台，了解免疫 通过提供对神经/免疫相互作用介导的独特见解来治疗其他神经系统疾病 通过MDSC，以及通过评估脑渗透免疫改变治疗策略。