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Immunotherapeutic targeting of MIF-dependent chaperone activity

MIF 依赖性伴侣活性的免疫治疗靶向

基本信息

批准号：
10633912
负责人：
ROBERT A MITCHELL
金额：
$ 35.59万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10633912
关键词：
ALS patients Acute Antibody Therapy Binding Biological Assay Biological Availability CTLA4 gene Cell Lineage Cell surface Cells Clinic Clinical Communities Cuprozinc Superoxide Dismutase Data Disease Progression Disease Resistance Drug Targeting Effector Cell Functional disorder Future Gene Expression Profile Genetic Transcription Homeostasis Human Hypoxia Immune Immune checkpoint inhibitor Immunosuppression Immunotherapeutic agent Immunotherapy In complete remission Individual Innate Immune Response Laboratories Lead Lesion Macrophage Malignant - descriptor Malignant Neoplasms Metabolic Metastatic Melanoma Migration Inhibitory Factor Mitochondria Modality Molecular Chaperones Monoclonal Antibodies Myelogenous Myeloid Cell Activation Myeloid Cells Myeloid-derived suppressor cells Neoplasm Metastasis Oral Pathway interactions Patients Phenocopy Phenotype Physiological Play Proteins Respiration Role Solid Solid Neoplasm Stromal Cells Structure-Activity Relationship Suicide Superoxide Dismutase T-Lymphocyte Testing Therapeutic Tissue-Specific Gene Expression Transgenic Organisms Tumor-associated macrophages analog angiogenesis antagonist anti-CTLA4 anti-CTLA4 antibodies anti-PD-1 anti-PD1 antibodies cancer immunotherapeutics cancer therapy combinatorial cytokine endoplasmic reticulum stress immune checkpoint blockade immunogenic immunoregulation improved inhibitor melanoma mitochondrial dysfunction monocyte mouse model mutant neovascularization neurotoxicity novel overexpression partial response polarized cell prevent programmed cell death protein 1 protein folding receptor response small molecule small molecule inhibitor stressor tumor tumor microenvironment tumor progression tumorigenic

项目摘要

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.

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