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

摘要：胶质母细胞瘤(Gbm)是最常见的脑部原发肿瘤，由于多种原因，其致死率一直很高。 因素，包括强大的免疫抑制微环境。在试图改变免疫激活的同时 已经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著增加 GBM患者的生存时间。这些结果显示了成功的关键临床障碍，并强调了 更好地了解免疫抑制的GBM微环境，这是一种独特的神经免疫的一部分 系统。GBM免疫抑制的中心是髓系来源的抑制细胞(MDSCs)的存在， 一种不成熟的血统，由单核细胞(M)和粒细胞(G)亚群组成，能有效抑制细胞毒 免疫反应。探讨MDSCs在GBM中的功能一直是本实验室研究的重点。vbl.使用 一种综合的方法，我们已经表明MDSCs与不良的GBM预后相关，驱动肿瘤干细胞 功能，并通过多个信号网络与肿瘤相互作用，这些信号网络可以中和增加 免疫激活。我们还询问了MDSC子集以揭示本地化和功能上的差异 以性别特定的方式，并确定可以改变以增强免疫力的MDSC子集信号程序 激活并减少GBM的生长。虽然我们的工作表明MDSCs是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，存在几个知识差距 仍然存在，解决它们是本应用程序的重点：尚不清楚MDSC是如何起源的，以及 其可塑性的程度；目前尚不清楚MDSC的谱系承诺是如何通过细胞内在程序和 由于与独特的神经微环境、微生物的相互作用和信号的相互作用而改变 程序；靶向MDSC亚群与免疫激活策略相结合的效果尚未 待定。这个应用程序的首要假设是MDSC子集的谱系承诺是 通过细胞固有的(包括性别特有的遗传和表观遗传程序)和细胞- 可以利用的外部(包括来自肠道-脑轴的系统性因素)相互作用 开发更有效的抗GBM疗法。通过这一R35机制，允许更长时间- 定期/灵活资助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 假说通过三个互补但综合的重点领域：(1)细胞和分子基础 MDSC的谱系承诺和可塑性，(2)MDSC对微环境线索的反应，以及(3)前- 临床MDSC靶向与免疫激活疗法相结合。这些研究立即产生了 对GBM和其他神经疾病的影响，并建立一个了解免疫的平台 通过提供对神经/免疫调节的相互作用的独特见解，对其他神经疾病的反应 通过MDSCs，以及通过评估脑穿透免疫改变治疗策略。

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.