(PQ5) Mitochondrial Heterogeneity in Melanoma Tumor and Immune Responses

(PQ5) 黑色素瘤肿瘤和免疫反应中的线粒体异质性

基本信息

批准号：
10471527
负责人：
Susan M Kaech
金额：
$ 7.95万
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：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471527
关键词：
Acidity Address Affect Animal Model Anti-Inflammatory Agents Apoptosis Biogenesis CD8B1 gene Cell Line Cells Cellular Metabolic Process Cellular Structures Cessation of life Chronic Complex Depressed mood Effectiveness Energy Metabolism Engineering Exhibits Gene Expression Genes Glucose Glycolysis Growth Growth Factor Heterogeneity Human Hypoxia Immune Immune response Immune system Immunologic Surveillance Immunosuppression Immunotherapy Individual Inflammation Interferons Knock-out Ligands Link Location Lymphocyte Function Major Histocompatibility Complex Malignant Neoplasms Mediating Melanoma Cell Metabolic Metabolism Microfluidics Mitochondria Mitochondrial DNA Modeling Movement Mus Natural Killer Cells Neoplasm Metastasis Nutrient Organelles Oxidation-Reduction Oxidative Phosphorylation Oxygen Pathway interactions Production Resistance Respiration Role Shapes Signal Transduction Skin Cancer Stress Stromal Cells Surface T cell response T-Lymphocyte Testing Therapeutic Tissues Tumor Immunity Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Warburg Effect Work anti-PD-1 anti-tumor immune response biological adaptation to stress cancer cell cancer risk cancer therapy cell growth cell type chemotherapy cytokine cytotoxic effector T cell environmental change environmental stressor extracellular fatty acid oxidation glucose metabolism immune checkpoint immune checkpoint blockade immunogenicity immunoreactivity innovation malformation melanoma mitochondrial metabolism mouse model neoplastic cell patient derived xenograft model programmed cell death ligand 1 programmed cell death protein 1 receptor response single cell technology tumor tumor growth tumor heterogeneity tumor initiation tumor metabolism tumor microenvironment tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY This proposal directly responds to RFA-CA-17-017 PQ5: How does mitochondrial heterogeneity influence tumorigenesis or progression? Tumor initiation, growth, death and metastasis are associated with significant changes in cell metabolism and signaling, central to which are mitochondria. Mitochondria are complex organelles that regulate energy metabolism, signaling and apoptosis, and contain mitochondrial DNA (mtDNA) that hardwires respiration and ATP production from within. It is often underappreciated that mitochondria in different cell types, and even within individual cells of the same type, vary in function and dynamics (location, shape and movement) basally and in response to stress. It is presently unclear how these aspects of mitochondrial heterogeneity contribute to tumorigenesis. Striking changes in glucose metabolism and mitochondrial respiration occur in tumors (the “Warburg effect”); however, these metabolic adaptations are neither uniform nor static. For example, mitochondria and metabolism of tumor cells, infiltrating immune cells and stromal cells, are diverse and responsive to ever-changing environmental stresses, including alterations in nutrient and oxygen availability, pH, and growth factors. The overarching theme of this proposal is that the heterogeneity in mitochondrial respiration, network dynamics and mtDNA-interferon (IFN) signaling not only affects cancer cell metabolism and growth, but also impacts their sensitivity to immune responses and immunotherapy. In Aim 1, unique mouse melanoma cell lines will be employed that exhibit significant differences in immunogenicity as well as mitochondrial respiration and mtDNA levels. In these cells, mitochondrial respiration will be activated or inhibited via knock-out of the Mcj or Cox10 genes, respectively, and tumor growth, immunoreactivity, and responses to anti-PD1 checkpoint blockade (immunotherapy) will be addressed to directly examine how mitochondrial heterogeneity links with immunogenicity/immunoevasion. Heterogeneity in mitochondrial dynamics and metabolism will also be assessed directly using microfluidic, single-cell approaches. Finally, as a potential therapeutic avenue to enhance anti-tumor immunity, T cells will be engineered to increase mitochondrial respiration and ATP production. In Aim 2, the focus will be on the role of mtDNA-stress mediated IFN signaling and whether it underlies differences in tumor growth, immune responses and sensitivity to immunotherapy. In Aim 3, models that pair patient-derived xenografts with their tumor infiltrating lymphocytes (PDX-TIL models) will be analyzed to probe the relevance of heterogeneity in mitochondrial respiration and mtDNA-stress signaling in human cancer. This work has the potential to illuminate new candidate pathways in tumor and immune cells to enhance anti-cancer therapies and stimulate anti-tumor immunity.

项目摘要该建议直接响应RFA-CA-17-017 PQ5：线粒体异质性如何影响肿瘤发生还是进展？肿瘤倡议，生长，死亡和转移与细胞代谢和信号传导的显着变化，这是线粒体的中心。是调节能量代谢，信号传导和凋亡的复杂细胞器，并包含线粒体 DNA（mtDNA）从内部呼吸和ATP产生。经常被低估了线粒体在不同的细胞类型中，甚至在同一类型的单个细胞中，功能上有所不同，动力学（位置，形状和运动）基本，并响应压力。提出不清楚线粒体异质性的这些方面如何导致肿瘤发生。引人注目的变化葡萄糖代谢和线粒体呼吸发生在肿瘤中（“ Warburg效应”）；但是，这些代谢适应既不均匀也不静态。例如，线粒体和肿瘤的代谢细胞，浸润的免疫细胞和基质细胞，潜水应力，包括养分和氧气可用性的改变，pH和生长因子。总体该提案的主题是线粒体呼吸，网络动力学和 mtDNA Interferon（IFN）信号传导不仅会影响癌细胞的代谢和生长，还会影响它们对免疫反应和免疫疗法的敏感性。在AIM 1中，独特的小鼠黑色素瘤细胞系将雇用暴露于免疫原性和线粒体显着差异的显着差异呼吸和mtDNA水平。在这些细胞中，线粒体呼吸将被激活或抑制 MCJ或COX10基因的敲除，以及肿瘤的生长，免疫反应性和对抗PD1检查点阻滞（免疫疗法）将被解决，以直接检查线粒体异质性与免疫原性/免疫抗性联系。线粒体动力学和还将使用微流体单细胞方法直接评估代谢。最后，作为潜力治疗途径增强抗肿瘤免疫，T细胞将被设计为增加线粒体呼吸和ATP产生。在AIM 2中，焦点将放在mtDNA压力介导的IFN信号转导的作用上以及它是否基于肿瘤生长，免疫复杂和对免疫疗法的敏感性的差异。在 AIM 3，将患者衍生的Xenographograptic与肿瘤浸润淋巴细胞（PDX-TIL模型）配对的模型将进行分析以探测异质性在线粒体呼吸和mtDNA压力中的相关性人类癌症的信号传导。这项工作有可能照亮肿瘤中的新候选途径免疫细胞可增强抗癌疗法并刺激抗肿瘤免疫组织切。