Mitochondrial Regulation of Interferon Response in Melanoma

黑色素瘤中干扰素反应的线粒体调节

基本信息

批准号：
10752523
负责人：
Melissa Johnson
金额：
$ 4.05万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
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：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752523
关键词：
ATAC-seq Acute Adaptive Immune System Affect Antigen Presentation Pathway Antioxidants Antitumor Response Autoimmune CD8-Positive T-Lymphocytes CRISPR screen Cellular Metabolic Process ChIP-seq Chromatin Chronic Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Dependence Development Down-Regulation Effectiveness Electron Transport Event Expression Profiling Fatty Acids Fluorescence Microscopy Heart Immune Evasion Immune response Immune system Immunosuppression Immunotherapy In Vitro Innate Immune System Interferon Type I Interferon Type II Interferon alpha Interferon-beta Interferons Knock-out Link Major Histocompatibility Complex Malignant Neoplasms Mediating Melanoma Cell Membrane Potentials Metabolic Metabolism Mitochondria Mus Oxidative Phosphorylation Pathway interactions Phenotype Phosphorylation Play Process Production Proteins RNA Reaction Reactive Oxygen Species Regulation Role Screening Result Signal Pathway Signal Transduction Skin Cancer Surface Testing Therapeutic Transcriptional Activation Tumor Immunity Up-Regulation Western Blotting Work anti-tumor immune response cancer cell cancer immunotherapy cancer therapy cell type desensitization fatty acid metabolism fatty acid oxidation improved in vivo insight melanoma metabolomics mitochondrial membrane mitochondrial metabolism neoplastic cell novel pharmacologic programmed cell death ligand 1 response therapy development transcription factor transcriptomics tumor tumor metabolism tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

PROJECT SUMMARY Interferons (IFNs) are central orchestrators of tumor immunity and can elicit both pro-tumor and anti-tumor responses depending on the cancer cell type, the type of IFN produced (e.g. a, b or g), duration of the signal, and other factors in the tumor microenvironment (TME). In their anti-tumor role, IFNs induce expression of major histocompatibility complex I (MHC-I) on the surface of tumor cells that mediates CD8+ T cell recognition and killing. Paradoxically, IFNs also upregulate expression of CD8+ T cell inhibitory surface molecules such as programmed death ligand 1 (PD-L1) to temper the immune response and avoid an autoimmune reaction. Thus, IFNs play a dual and opposing role in cancer development, making a more complete understanding of the contexts in which their pro- or anti-tumor functions predominate important for effective cancer therapy development. Immune evasion can occur when malignant cells lose MHC-I and antigen processing and presentation (APP) machinery or otherwise become desensitized to IFN signaling. Thus, finding ways to reinvigorate these pathways has significant therapeutic potential. Interestingly, recent work from the sponsor’s lab and others has shown that mitochondrial electron transport chain activity is required for IFN-induced MHC-I expression. In addition, preliminary data show that chronic IFN stimulation in vitro reduces mitochondrial oxidative phosphorylation (OXPHOS) in melanoma cells, suggesting that IFN signaling can also influence tumor mitochondrial metabolism. To probe this novel regulatory link between the metabolic state of tumor cells and their responses to IFN, a metabolism-targeted CRISPR knock-out screen was performed in mouse melanoma cells. Results from this screen not only confirmed a requirement for mitochondrial OXPHOS in regulating IFN signaling, but also implicated fatty acid metabolism and ROS. Based on these preliminary data, it is proposed that mitochondrial OXPHOS, specifically mitochondrial fuel utilization and ROS production, can directly regulate key IFN signaling steps, and that chronic IFN exposure leads to changes in mitochondrial metabolism that facilitate immune evasion in melanoma. This overall hypothesis will be tested through completion of two specific aims. Aim 1 is to determine which steps in the IFN signaling pathway are subject to mitochondrial OXPHOS- mediated regulation and the precise mitochondrial metabolic signals involved. Aim 2 is to determine how reduced mitochondrial OXPHOS and/or increased mitochondrial ROS are generating a suppressive tumor microenvironment and if chronic type I IFN signaling elicits similar immunosuppressive effects as chronic type II IFN exposure. This project will provide important new insights into the relationship between mitochondrial metabolism and IFN responses during tumor progression that might be exploited to improve or reactivate anti- tumor immune responses for better cancer treatment and augment cancer immunotherapy.