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

• 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
• 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

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 在美国，肺癌是主要的死亡原因，也是第二常见的癌症。 免疫疗法的应用显著提高了癌症患者的存活率。然而， 进一步需要对目前的免疫疗法取得更好的反应。最有希望的结果是 在将抗PD-L1/PD-1与激活免疫功能的治疗相结合时实现了这一点。 我们认为，外源性一氧化碳(Coex)在低剂量无毒应用是一种潜在的 用于免疫治疗的肺癌患者的佐剂。一氧化碳是由血红素内源产生的 加氧酶-1(HO-1)，在动态平衡期间将血红素分解为三种活性代谢物。我们有 证明Coex以250ppm的速度每天持续1小时(相当于获得的CO剂量 燃烧2支香烟)可阻止肺癌和前列腺癌的进展。Coex可通过以下途径抑制肿瘤生长 靶向癌细胞的新陈代谢。然而，由于Coex阻止了不同类型肿瘤的生长，并且在 不同的代谢率以及在体内比体外更有效地诱导癌细胞凋亡，我们 推论Coex在包括免疫细胞在内的TME中具有更广泛的影响。我们的初步数据表明 COEX促进更多的“免疫接受型”肿瘤微环境(TME)。我们建议重新编排 TME通过调节血红素代谢来调节对免疫治疗的反应。 我们的目标是： 确定Coex在重定向免疫反应中的作用，以提高免疫治疗的有效性。 具体地说，我们打算： I)确定Coex与抗CTLA-4、抗PD-L1或抗PD-1联合治疗在 小鼠肺癌模型。 Ii)确定免疫治疗应答过程中Coex通过mTOR-Notch1信号对CD86的诱导 在肺癌模型中。 Iii)确定内源性HO-1衍生的CO在免疫治疗应答过程中的重要性。 本申请中提出的研究将描绘CO和HO-1在宿主激活中的作用 免疫反应通过选择性信号通路导致TME中髓系功能的增加。我们的 研究结果将对肺癌患者具有基础和治疗意义，特别是Coex是 在临床试验中。这项研究与NCI和RFA的使命很好地结合在一起。 翻译探索性/发展性研究(R21临床试验可选)“(PAR-19-356)。