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

项目摘要：胶质母细胞瘤 (GBM) 是最常见的原发性恶性脑肿瘤，中位数 生存期长达20个月。男性 GBM 发病率是女性的 1.6 倍，甚至更糟 疾病结果。标准护理治疗和免疫疗法目前正处于临床试验阶段， 在改善患者预后方面取得的成功有限。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耐药的基础。虽然 骨髓源性抑制细胞（MDSC）在恶性肿瘤患者体内积聚，并在 这种免疫抑制环境的建立，个体 MDSC 亚群促进的机制 肿瘤发生仍不清楚。在临床前模型中，我证明单核细胞 MDSC (mMDSC) 男性中肿瘤浸润率更高，而粒细胞 MDSC (gMDSC) 在男性中更丰富 女性的末梢循环。此外，肿瘤中有更多的免疫抑制性骨髓细胞 男性患者的 gMDSC 基因特征与女性患者的不良预后相关。 MDSC子集 变异还决定了临床前模型中的性别特异性治疗反应，包括对氟达拉滨和 抗IL-1β。我还确定补体成分 1q (C1q) 在 gMDSC 中高度表达，并且升高 在女性中。基于这些观察，我假设 MDSC 亚群通过以下方式促进 GBM 进展： 以性别特异性的方式发现不同的机制，并且它们的靶向将提高 T 细胞激活的功效 策略。具体目标 1 将检验以下假设：mMDSC 和 gMDSC 在局部和局部疾病中具有不同的作用。 以性别特异性方式进行全身性免疫抑制。该目标将研究肿瘤生长的变化， 通过过继转移 MDSC 子集并选择性消耗来测量血管密度和免疫激活状态 骨髓嵌合体中的 MDSC。具体目标 2 将检验以下假设：独特的基因表达 MDSC 子集的特征使它们容易受到可与检查点组合的不同药物的影响 调制器。子目标 2A 将检查候选药物在体外和体内对 MDSC 活性的功效，同时 Sub-Aim 2B将尝试通过结合MDSC靶向来实现持久的抗肿瘤免疫反应 抗 PD-1、抗 CTLA-4 和抗 OX40 策略。具体目标 3 将检验以下假设：gMDSC- 衍生的 C1q 通过评估肿瘤促进 MDSC 谱系定型和全身免疫抑制 C1q 缺失时的进展和检查点反应。 Sub-Aim 3A将使用C1qa敲除骨髓 和 C1q 受体抑制剂来确定 MDSC 的命运。 Sub Aim 3B将联合使用药物抑制剂 与检查点调制器。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、重新利用来开发 GBM 的新型免疫疗法 药物并定义靶向途径。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治疗效果。

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.