Role of myeloid-derived suppressor cells in local and systemic immunosuppression in glioblastoma

项目摘要：胶质母细胞瘤(GBM)是最常见的原发恶性脑肿瘤，中位数为 存活时间长达20个月。男性的GBM发病率是女性的1.6倍，情况更糟 疾病结局。目前正在进行临床试验的标准护理治疗和免疫疗法 改善患者预后的成功有限。促进肿瘤生长的免疫抑制微环境 进展和限制抗肿瘤免疫反应可能是治疗抵抗的基础。虽然 髓系来源的抑制细胞(MDSCs)在恶性肿瘤患者体内积聚，在肿瘤的发生、发展中起关键作用。 这种免疫抑制环境的建立以及单个MDSC亚群促进免疫的机制 肿瘤的发生仍然没有明确的定义。在临床前模型中，我证明了单核细胞MDSCs(MMDSCs) 男性浸润性肿瘤的发生率较高，而粒细胞多向干细胞(GMDSCs)在 女性的外周循环。此外，肿瘤中有更多的免疫抑制髓系细胞。 男性患者和gMDSC基因特征与女性患者预后不良相关。MDSC子集 变异也决定了临床前模型中性别特异性的治疗反应，包括对氟达拉滨和 抗IL-1β。我还证实了补体成分1q(C1q)在gMDSCs中高度表达并升高 在雌性身上。基于这些观察，我假设MDSC子集通过以下方式促进GBM进展 性别特异性的不同机制以及它们的靶向性将提高T细胞激活的效率 战略。特定目标1将检验以下假设：mMDSCs和gMDSCs在局部和 全身性免疫抑制以一种性别特有的方式。这一目标将研究肿瘤生长的变化， 过继转移MDSC亚群和选择性去除MDSC对血管密度和免疫激活状态的影响 骨髓嵌合体中的MDSCs。《特定目标2》将检验这样一种假设：独特的基因表达 MDSC亚集的特征使其对可与Checkpoint结合的不同药物敏感 调制器。次级目标2A将检查候选药物在体外和体内对MDSC活性的效果，而 子目标2B将尝试通过结合MDSC靶向来实现持久的抗肿瘤免疫反应 使用抗PD-1、抗CTLA-4和抗OX40的策略。具体目标3将检验gMDSC- 通过评估肿瘤，衍生的C1q促进MDSC的谱系承诺和全身免疫抑制 在没有C1q的情况下进度和检查点响应。SubAim 3A将使用C1qa基因敲除骨髓 和C1q受体抑制剂来决定MDSC的命运。SubAim 3B将联合使用药物抑制剂 带有检查点调制器。这些研究为我未来的研究计划和 通过解决抗肿瘤免疫的变化，重新定位来开发治疗基底膜的新型免疫疗法 药物和确定靶向途径。这些结果广泛适用于其他癌症，并可能导致 先进的治疗机会和改善的患者结局。

PROJECT SUMMARY: Glioblastoma (GBM) is the most common primary malignant brain tumor, with a median survival of up to 20 months. Males have a 1.6-fold higher incidence of GBM compared to females and worse disease outcome. Standard-of-care treatment and immunotherapies, which are currently in clinical trials, have had limited success improving patient outcome. An immunosuppressive microenvironment facilitating tumor progression and restricting anti-tumor immune response likely underlies therapeutic resistance. Although myeloid-derived suppressor cell (MDSCs) accumulate in patients with malignancies and play a critical role in the establishment of this immunosuppressive milieu, the mechanisms by which individual MDSC subsets promote tumorigenesis remain poorly defined. In pre-clinical models, I demonstrated that monocytic MDSCs (mMDSCs) infiltrated tumor at higher rates in males, while granulocytic MDSCs (gMDSCs) were more abundant in the peripheral circulation of females. Furthermore, there were more immunosuppressive myeloid cells in the tumors of male patients and gMDSC gene signature associated with poor prognosis of female patients. MDSC subset variation also determined sex-specific therapeutic response in preclinical models, including to fludarabine and anti-IL-1β. I also established that complement component 1q (C1q) is highly expressed by gMDSCs and elevated in females. Based on these observations, I hypothesize that MDSC subsets promote GBM progression via distinct mechanisms in a sex-specific manner and that their targeting will improve the efficacy of T cell-activating strategies. Specific Aim 1 will test the hypothesis that mMDSCs and gMDSCs have distinct roles in local and systemic immunosuppression in a sex-specific manner. This aim will investigate the changes in tumor growth, vascular density and immune activation status by adoptively transferring MDSC subsets and selectively depleting MDSCs in bone marrow chimeras. Specific Aim 2 will test the hypothesis that the unique gene expression signatures of MDSC subsets makes them susceptible to distinct drugs that can be combined with checkpoint modulators. Sub-Aim 2A will examine the efficacy of drug candidates on MDSC activity in vitro and in vivo, while Sub-Aim 2B will attempt to achieve durable anti-tumor immune response by combining MDSC targeting strategies with anti-PD-1, anti-CTLA-4 and anti-OX40. Specific Aim 3 will test the hypothesis that gMDSC- derived C1q promotes MDSC lineage commitment and systemic immunosuppression by evaluating tumor progression and checkpoint response in the absence of C1q. Sub-Aim 3A will use C1qa knockout bone marrow and C1q receptor inhibitors to determine MDSC fate. Sub Aim 3B will use pharmacological inhibitors combined with checkpoint modulators. These studies lay the foundation for my future research program and the development of novel immunotherapies for GBM by addressing variations in anti-tumor immunity, repurposing drugs and defining targetable pathways. These results are broadly applicable to other cancers and can lead to advanced treatment opportunities and improved patient outcome.