Determining the role of gas metabolite in response to immunotherapy

确定气体代谢物在免疫治疗中的作用

基本信息

批准号：
10316249
负责人：
Barbara Wegiel
金额：
$ 24.05万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-09 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10316249
关键词：
Adjuvant Affect Anti-Inflammatory Agents Antibodies Apoptosis CD3 Antigens CD86 gene Cancer Model Cancer Patient Carbon Monoxide Cause of Death Cell physiology Cells Cigarette Clara cell Clinical Clinical Trials Cytomegalovirus Data Degradation Pathway Dose Exploratory/Developmental Grant Extracellular Signal Regulated Kinases FRAP1 gene Gases Gene Expression Growth Heme High Prevalence Homeostasis Hour Hypoxia Immune Immune response Immunosuppression Immunotherapy In Vitro Inflammation Inflammatory Innate Immune Response Investigation KRAS2 gene Knockout Mice Ligands Lung Neoplasms Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mass Spectrum Analysis Measures Mediating Mediator of activation protein Metabolic Metabolism Mission Modeling Molecular Mus Mutation Myelogenous Myeloid Cells Outcome Pathway interactions Patients Phenotype Proliferation Marker Protein Kinase Proteins RNA Resistance RiboTag Ribosomes Role Scheme Shapes Signal Pathway Signal Transduction Sirolimus Small Interfering RNA Smoker Smoking Stains T-Lymphocyte Technology Therapeutic Tobacco smoke Tobacco smoking behavior Transforming Growth Factor beta United States angiogenesis anti-CTLA4 anti-PD-1 anti-PD-1/PD-L1 anti-PD-L1 anti-PD1 therapy antitumor effect cancer cell cancer survival carcinogenesis inhibitor cell type effectiveness evaluation genetic signature glucose metabolism heme oxygenase-1 immune function immunoregulation improved improved outcome in vivo inhibitor lipid metabolism lung Carcinoma macrophage metabolic rate mouse model neutralizing antibody novel pembrolizumab prevent recruit response tumor tumor growth tumor metabolism tumor microenvironment

项目摘要

Project Summary Lung cancer is a leading cause of death and the second most common cancer in the United States. Application of immunotherapies has led to significant improvement in survival of cancer patients. However, there is further need to achieve better responses to current immunotherapies. The most promising results had been achieved when combining anti-PD-L1/PD-1 with treatments that activate immune function. We propose that exogenous carbon monoxide (COex) applied at low non-toxic doses is a potential adjuvant for patients with lung cancer treated with immunotherapy. CO is generated endogenously by heme oxygenase-1 (HO-1) that acts during homeostasis to break down heme to three active metabolites. We have demonstrated that COex applied at 250 ppm for 1 hour per day (that corresponds to the dose of CO obtained from burning 2 cigarettes) blocks progression of lung and prostate cancers. COex can block tumor growth via targeting metabolism of cancer cells. However, since COex blocks growth of different tumor types and at various metabolic rates as well as is more efficient in vivo than in vitro in inducing apoptosis of cancer cells, we reasoned COex has a broader effect in the TME that includes immune cells. Our preliminary data suggest that COex promotes more ‘immuno-receptive’ tumor microenvironment (TME). We propose that reprograming of the TME by regulating heme metabolism regulates responses to immunotherapy. Our aim is to: To determine the role of COex in redirecting immune responses to increase efficacy of immunotherapy. Specifically, we intent to: i) Determine effectiveness of the combination of COex and anti-CTLA-4, anti-PD-L1 or anti-PD-1 treatment in a mouse model of lung cancer. ii) Determine COex-mediated induction of CD86 via mTOR-Notch1 signaling during response to immunotherapy in the lung cancer model. iii) Define the importance of endogenous HO-1-derived CO during response to immunotherapy. The investigations proposed in this application will delineate the role of CO and HO-1 in activation of the host immune responses via selective signaling pathways leading to increase in myeloid function in the TME. Our findings will have fundamental and therapeutic implications for patients with lung cancer, especially that COex is in clinical trials. This study is well-aligned with the mission of the NCI and this RFA “NCI Clinical and Translational Exploratory/Developmental Studies (R21 Clinical Trial Optional)” (PAR-19-356).

项目摘要肺癌是死亡的主要原因，也是美国第二常见的癌症。免疫疗法的应用导致癌症患者的存活率显着提高。然而，进一步需要对当前免疫疗法做出更好的反应。最有希望的结果是当将抗PD-L1/PD-1与激活免疫功能的处理结合时，可以实现。我们建议以低无毒剂量施用的外源性碳一氧化碳（COEX）是一种潜力调整接受免疫疗法治疗的肺癌患者。 CO由血红素内源性产生氧合酶-1（HO-1）在体内稳态过程中起作用，将血红素分解为三个活性代谢产物。我们有证明COEX每天以250 ppm的速度应用1小时（对应于获得的CO的剂量燃烧2支香烟）阻止肺和前列腺癌的进展。 COEX可以通过靶向癌细胞的代谢。但是，由于COEX阻止了不同肿瘤类型的生长和AT 在癌细胞诱导的凋亡中，各种代谢率和体内效率更高，我们理性的COEX在包括免疫细胞的TME中具有更广泛的作用。我们的初步数据表明 COEX促进了更多的“免疫感应”肿瘤微环境（TME）。我们提出了重新编程通过调节血红素代谢来调节对免疫疗法的反应。我们的目标是：确定COEX在重定向免疫复杂以提高免疫疗法效率方面的作用。具体而言，我们意图： i）确定COEX和抗CTLA-4，抗PD-L1或抗PD-1处理的有效性肺癌的小鼠模型。 ii）通过MTOR-NOTCH1信号在对免疫疗法的反应期间通过MTOR-NOTCH1信号确定COEX介导的诱导在肺癌模型中。 iii）定义了对免疫疗法反应期间内源性HO-1衍生CO的重要性。本申请中提出的投资将描述CO和HO-1在激活主机中的作用通过选择性信号通路的免疫反应，导致TME中髓样功能的增加。我们的发现将对肺癌患者具有根本和治疗的影响，尤其是COEX是在临床试验中。这项研究与NCI和RFA“ NCI临床和转化探索/发育研究（R21临床试验可选）”（PAR-19-356）。