Immunotherapeutic targeting of MIF-dependent chaperone activity

项目摘要 “MIF-dependent chaperone activity的免疫靶向” 有利于线粒体呼吸的代谢重编程在控制线粒体呼吸中起着重要作用。 髓系细胞中的差异基因表达模式。我们最近的研究发现了一种新的蛋白质 一种间接控制线粒体稳态和代谢程序的伴侣蛋白依赖性途径 这是驱动最大肿瘤内髓样细胞免疫抑制表型所需的。我们的假设 预测这种分子伴侣活性的小分子抑制，由多功能细胞因子MIF进行， 诱导自发的Cu/Zn超氧化物歧化酶（SOD 1）错误折叠和异常的线粒体结合 导致代谢重编程和随后的肿瘤内骨髓细胞免疫表型逆转， 抑制表型转化为免疫刺激表型。本申请中提出的研究将：1） 描述基于4-IPP的MIF分子伴侣抑制剂在MIF/SOD 1背景下的作用机制- 依赖性TAM/MDSC极化; 2）确定缺氧作为生理性ER的相对贡献 在MIF和4-IPP的情况下加剧骨髓wt SOD 1错误折叠的应激物，和3）评估 先导MIF伴侣蛋白拮抗剂作为个体和组合形式对 转移性黑色素瘤

PROJECT SUMMARY “Immunotherapeutic targeting of MIF-dependent chaperone activity” Metabolic reprogramming that favors mitochondrial respiration plays an important role in controlling differential gene expression patterns in myeloid lineage cells. Our recent findings have identified a novel protein chaperone-dependent pathway that indirectly controls mitochondrial homeostasis and metabolic programming that are needed to drive maximal intratumoral myeloid cell immune suppressive phenotypes. Our hypothesis predicts that small molecule inhibition of this chaperone activity, carried out by the multifunctional cytokine MIF, induces spontaneous Cu/Zn superoxide dismutase (SOD1) misfolding and aberrant mitochondrial binding leading to metabolic reprogramming and subsequent phenotypic reversion of intratumoral myeloid cell immune suppressive phenotypes into immune stimulatory phenotypes. Studies proposed in this application will: 1) Delineate the mechanisms of action of 4-IPP-based MIF chaperone inhibitors in the context of MIF/SOD1- dependent TAM/MDSC polarization; 2) Determine the relative contribution of hypoxia as a physiologic ER stressor that exacerbates myeloid wt SOD1 misfolding in the context of MIF and 4-IPP, and 3) Evaluate the therapeutic potential of lead MIF chaperone antagonists as individual and combinatorial modalities against established metastatic melanoma.