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

基本信息

批准号：
10615850
负责人：
Justin D. Lathia
金额：
$ 65.47万
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：
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/10615850
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 Infiltration Knowledge Laboratories Malignant neoplasm of brain Mediating Molecular Myeloid-derived suppressor cells Nervous System 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 neural neuroinflammation novel therapeutics pre-clinical proctolin programs response sex stem cell function success therapeutic target tumor tumor growth

项目摘要

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，由于许多因素，包括有效的免疫抑制微环境。试图改变免疫激活在其他高级癌症中取得了成功，一系列不同的策略尚未明显增加 GBM患者生存。这些结果证明了成功的关键临床障碍，并强调了更好地了解免疫抑制GBM微环境，这是独特的神经免疫的一部分系统。 GBM免疫抑制的中心是髓样衍生的抑制细胞（MDSC）的存在，由单核细胞（M）和粒细胞（G）子集组成的未成熟谱系，可有效抑制细胞毒性免疫反应。询问MDSC在GBM中的功能一直是我们实验室的主要重点。使用一种综合方法，我们已经表明，MDSC与GBM预后不良，驱动癌症干细胞功能，并通过多个信号网络与肿瘤相互作用，这些信号网络可以被中和以增加免疫激活。我们还询问了MDSC子集以揭示本地化和功能的差异以性别特定的方式并确定了可以更改以增加免疫的MDSC子集信号传导程序激活并降低GBM的生长。虽然我们的工作牵涉到MDSC作为GBM的生物标志物和驱动因素进步并确定它们是下一代治疗靶标，有几个知识差距保留并解决它们是此应用程序的重点：尚不清楚MDSC如何起源和其可塑性的程度；目前尚不清楚如何通过细胞中的程序和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而改变了程序；以及将MDSC子集与免疫激活策略结合使用的功效尚未要确定。该应用程序的总体假设是MDSC子集谱系承诺是通过细胞中的整合（包括性别特异性遗传和表观遗传程序）和细胞的驱动可以利用的外部（包括来自肠道轴的全身因素）相互作用开发更有效的抗GBM疗法。通过这种R35机制，该机制允许更长术语/灵活的资金以开发具有协同潜力的平行区域，我们将测试其中的不同方面假设虽然三个互补但集成的重点区域：（1）细胞和分子基础 MDSC谱系承诺和可塑性，（2）MDSC对微环境提示的响应，以及（3）临床MDSC靶向与免疫激活疗法结合使用。这些研究立即对GBM和其他神经系统疾病的影响，并建立了理解免疫的平台通过为介导的神经/免疫相互作用提供独特的见解，在其他神经系统疾病中的反应通过MDSC以及通过评估改变脑部免疫的治疗策略。