The immunosuppressive role of glioblastoma-derived macrophage migration inhibitor factor

项目概要 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- 接受标准护理治疗（包括手术、放疗和化疗）15 个月。下 生理条件下，免疫系统的目的是清除不规则的癌细胞；然而，肿瘤 已经进化出阻止免疫反应的机制。我们的实验室之前鉴定出骨髓源性 抑制细胞（MDSC）作为 GBM 外周血和肿瘤中的免疫抑制细胞群 与生存率和免疫反应下降相关的微环境。巨噬细胞迁移 抑制因子（MIF）被确定为促进 MDSC 激活的 GBM 衍生因子。我 假设 MIF 通过激活 CD74 和 CXCR2 诱导并激活 MDSC 受体，驱动 GBM 的免疫抑制表型。目标 1 将检验 MIF 的假设 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 适合 GBM 衍生的 MDSC 的研究。该系统可以快速生产 MDSC 生物学重复研究 MIF 及其受体在增强 MDSC 增殖和 MDSC 中的作用 功能。目标 2 将检验 MIF 受体对于体内 GBM 免疫抑制至关重要的假设 通过分析 GBM 微环境中的存活率和免疫细胞浸润。这些结果将 确定这些受体是否是未来旨在减少 MDSC 的免疫疗法的目标 人群以增强免疫反应。基于之前确定 MIF 信号轴的研究 作为 GBM 微环境和体外共培养系统中 MDSC 激活的调节剂 和分泌 MIF 的神经胶质瘤小鼠模型，我处于研究 MIF 信号轴的最佳位置 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.