The immunosuppressive role of glioblastoma-derived macrophage migration inhibitor factor

项目总结 胶质母细胞瘤(GBM)是最常见的原发恶性脑肿瘤，中位生存期仅为12-12个月。 15个月，接受包括手术、放疗和化疗在内的标准护理治疗。在……下面 在生理条件下，免疫系统旨在清除不规则的癌细胞；然而，肿瘤 进化出了阻止免疫反应的机制。我们的实验室之前发现了髓系来源的 GBM外周血和肿瘤中作为免疫抑制细胞群的抑制细胞(MDSCs) 与存活率和免疫反应降低相关的微环境。巨噬细胞迁移 抑制因子(MIF)被确定为促进MDSC活化的GBM衍生因子。我 假设MIF通过激活CD74和CXCR2诱导和激活MDSCs 受体，驱动GBM的免疫抑制表型。目标1将检验MIF的假设 通过使用我有的体外共培养系统，信号对MDSCs的诱导和激活至关重要 适合GBM来源的MDSCs的研究。该系统允许快速生产MDSCs 生物复制研究MIF及其受体在促进MDSC增殖和MDSC中的作用 功能。Aim 2将验证MIF受体在体内对GBM免疫抑制是必不可少的假设 通过分析小鼠在GBM微环境中的存活情况和免疫细胞的浸润情况。这些结果将 确定这些受体是否是未来旨在减少MDSC的免疫疗法的靶点 增强人群的免疫反应。基于先前确定MIF信号轴的研究 在GBM微环境和体外共培养体系中作为MDSC激活的调节剂 和分泌MIF的小鼠胶质瘤模型，我处于研究MIF信号轴的最佳位置 以及它如何影响MDSC的诱导、激活和免疫抑制。

PROJECT SUMMARY Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and has a median survival of only 12- 15 months with the standard-of-care therapies including surgery, radiation, and chemotherapy. Under physiological conditions, the immune system is intended to remove irregular cancerous cells; however, tumors have evolved mechanisms to halt the immune response. Our laboratory previously identified myeloid-derived suppressor cells (MDSCs) as an immune suppressive cell population in GBM peripheral blood and the tumor microenvironment that correlates with decreased survival and immune response. Macrophage migration inhibitory factor (MIF) was determined to be a GBM-derived factor that promoted MDSC activation. I hypothesize that MIF induces and activates MDSCs through activation of the CD74 and CXCR2 receptors, driving the immune suppressive phenotype in GBM. Aim 1 will test the hypothesis that MIF signaling is critical for the induction and activation of MDSCs by the use of an in vitro co-culture system I have adapted for the study of GBM-derived MDSCs. This system allows for the rapid production of MDSCs in biological replicates to study the role of MIF and its receptors in enhancing MDSC proliferation and MDSC function. Aim 2 will test the hypothesis that MIF receptors are essential for GBM immune suppression in vivo by analyzing survival along with immune cell infiltration in the GBM microenvironment. These results will identify whether these receptors are a target for future immune therapies aimed at reducing the MDSC population to enhance the immune response. Based on previous studies that identified the MIF signaling axis as a moderator of MDSC activation within the GBM microenvironment and with the in vitro co-culture system and a MIF-secreting mouse model of glioma, I am in an optimal position to investigate the MIF signaling axis and how it affects MDSC induction, activation, and immune suppression.