Breaking down tumor immune privilege through targeted hypoxia reduction

通过有针对性的减少缺氧来打破肿瘤免疫特权

• 批准号: 10202534
• 负责人: Michael A Curran
• 金额: $ 48.17万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10202534
• 关键词: Activities of Daily Living; Angiogenesis Inhibitors; Animals; Automobile Driving; Blood; CTLA4 gene; Cancer Model; Cell Density; Cell Hypoxia; Cells; Cellular Metabolic Process; Clinical; Clinical Trials; Complex; Consumption; Coupled; Elements; Equilibrium; Failure; Fibroblasts; Fostering; Glycolysis; Hypoxia; Image; Immune; Immunotherapy; In Vitro; Intervention; Kinetics; Knock-out; Knowledge; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Maps; Measures; Mediating; Memory; Metabolic; Metabolism; Metformin; Molecular; Mus; Myelogenous; Myeloid Cells; Myeloproliferative disease; Myofibroblast; Natural Killer Cells; Outcome; Oxidative Phosphorylation; Oxygen; Oxygen Consumption; Patients; Phenotype; Process; Prodrugs; Prostatic Neoplasms; Radiation therapy; Resistance; Retreatment; Role; Signal Transduction; Source; T-Lymphocyte; Therapeutic; Time; Tissues; Tumor Immunity; Tumor-infiltrating immune cells; Work; fitness; hypoxia inducible factor 1; immune checkpoint blockade; improved; in vivo; inhibitor/antagonist; insight; mouse model; neoplastic cell; normoxia; pancreatic cancer model; pancreatic neoplasm; programs; prostate cancer model; refractory cancer; response; restoration; subcutaneous; transcription factor; tumor; tumor hypoxia; tumor metabolism; tumor progression

PROJECT SUMMARY/ABSTRACT Tumor hypoxia predicts poor outcomes across all cancers and is a well-established source of resistance to both chemo- and radiotherapy. We have shown that T cells fail to thrive in hypoxic zones of cancer underlying the failure of checkpoint blockade for immune “cold” indications such as pancreatic and prostate cancer. While our prior work relied on our serendipitous discovery that the hypoxia-activated prodrug, TH-302, could efficiently reduce tumor hypoxia, there have been no studies to identify the most effective means to reduce hypoxia in cancer. Mechanistically, tumor hypoxia results from the combination of diminished oxygen supply coupled with enhanced tumor oxygen consumption. While each of these influences helps to foster hypoxia and nucleate an immune suppressive state, nothing is known of their relative importance in establishment of the hypoxic state itself, nor of their differential impact on tumor-infiltrating T cells within hypoxic regions. Further, we lack an understanding of the factors governing durability of hypoxia-reduction, and of any interventions to limit tumors’ capacity to restore the hypoxic state. At a deeper level, the precise molecular signals triggered by hypoxia, which reprogram myeloid and myofibroblast cells in the stroma to adapt metabolically to the hypoxic state and acquire immune suppressive function also remain unclear. We therefore hypothesize that tumor hypoxia and associated immune suppressive programming of the myeloid and myofibroblast stroma can be reduced through both local tissue remodeling and through limitation of tumor oxygen metabolism. Our first aim is to determine the kinetics of hypoxia and immune infiltrate modulation by hypoxia-activated prodrugs, oxidative phosphorylation (OxPhos) inhibitors, and anti-angiogenic agents. For each class, we will establish the kinetics by which they reduce hypoxia, how durable that reduction is post-therapy, and whether re-treatment can eliminate re-emergent hypoxia. This first of its kind systematic study will not only reveal optimal approaches for reducing tumor hypoxia in an immune-potentiating context but will also provide insights into the relative contribution of disrupted oxygen supply versus elevated tumor oxygen consumption toward establishing hypoxia. Second, we will investigate the impact of OxPhos inhibitors on both tumor and T cell metabolism and hypoxic fitness. We will assess how three inhibitors of OxPhos metabolism, which target distinct subunits of Complex I, impact tumor versus T cell metabolism, function, and hypoxic adaptation. These studies will provide critical insight into whether tumor oxygen consumption can be inhibited in a manner which compromises tumor hypoxic fitness and immune privilege without damaging the functional capacity of anti-tumor immunity. The third aim of this proposal utilizes mice lacking hypoxia-inducible factor 1-alpha (HIF1α) or HIF2α in either their tumor myeloid stroma or myofibroblasts to map the downstream signals responsible for functional and metabolic programming of these cells in response to hypoxia. These studies will provide critical insights allowing clinical hypoxia reduction to improve and with it our capacity for immunotherapy of “cold” cancers.

项目总结/文摘