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

胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤， 生存期长达20个月。男性GBM的发病率是女性的1.6倍， 疾病结果。目前正在临床试验中的标准治疗和免疫疗法， 改善患者预后的成功率有限。免疫抑制微环境促进肿瘤 进展和限制抗肿瘤免疫应答可能是治疗抗性的基础。虽然 骨髓源性抑制细胞（MDSC）在恶性肿瘤患者中积累，并在肿瘤的发生和发展中起关键作用。 建立这种免疫抑制环境，单个MDSC亚群促进免疫抑制的机制， 肿瘤发生仍然定义不清。在临床前模型中，我证明了单核细胞MDSC（mMDSC） 在男性中，浸润性肿瘤的发生率更高，而粒细胞MDSC（gMDSC）在男性中更丰富。 女性的外周循环此外，肿瘤中有更多的免疫抑制性髓样细胞 gMDSC基因特征与女性患者预后不良相关。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。我还确定了补体成分1 q（C1 q）在gMDSC中高度表达，并在GMDSC中升高。 在女性中。基于这些观察，我假设MDSC亚群通过以下途径促进GBM进展： 它们的靶向作用将改善T细胞活化的功效， 战略布局具体目标1将检验mMDSC和gMDSC在局部和局部分化中具有不同作用的假设。 以性别特异性方式进行全身免疫抑制。这一目标将研究肿瘤生长的变化， 通过过继转移MDSC亚群和选择性耗竭MDSC， 骨髓嵌合体中的MDSC。具体目标2将检验以下假设： MDSC亚群的特征使其对可与检查点结合的不同药物敏感 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， 子目标2B将尝试通过结合MDSC靶向， 抗PD-1、抗CTLA-4和抗OX 40的策略。具体目标3将检验gMDSC- 衍生C1 q通过评估肿瘤促进MDSC谱系定型和全身免疫抑制 C1 q缺失时的进展和检查点反应。子目标3A将使用C1 qa敲除骨髓 和C1 q受体抑制剂来确定MDSC的命运。子目标3B将联合使用药理学抑制剂 检查点调制器。这些研究为我今后的研究计划和 通过解决抗肿瘤免疫的变化， 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.