The immunosuppressive role of glioblastoma-derived macrophage migration inhibitor factor

项目摘要 胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤，中位生存期仅为12- 20年。 15个月的标准治疗，包括手术，放疗和化疗。下 在生理条件下，免疫系统旨在去除不规则的癌细胞;然而，肿瘤 已经进化出了阻止免疫反应的机制我们的实验室以前发现骨髓源性 抑制细胞（MDSC）作为GBM外周血中的免疫抑制细胞群， 微环境与生存和免疫反应下降相关。巨噬细胞移动 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CD 74和CXCR 2诱导并激活MDSC 受体，驱动GBM中的免疫抑制表型。目标1将检验MIF 信号传导对于使用体外共培养系统诱导和激活MDSC至关重要 适用于GBM衍生的MDSC的研究。该系统允许MDSC的快速生产， 生物学重复以研究MIF及其受体在促进MDSC增殖和MDSC分化中的作用。 功能目的2将验证MIF受体在体内GBM免疫抑制中所必需的假设 通过分析存活沿着免疫细胞在GBM微环境中的浸润。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 以增强免疫反应。基于先前确定MIF信号轴的研究， 作为GBM微环境中MDSC活化的调节剂，并与体外共培养系统一起使用 和分泌MIF的胶质瘤小鼠模型，我处于研究MIF信号传导轴的最佳位置。 以及它如何影响MDSC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.