Determining the role of gas metabolite in response to immunotherapy

项目摘要 肺癌是导致死亡的主要原因，也是美国第二大常见癌症。 免疫疗法的应用已导致癌症患者的存活率显著改善。然而，在这方面， 还需要实现对当前免疫疗法的更好应答。最有希望的结果是 当抗PD-L1/PD-1与激活免疫功能的治疗相结合时， 我们认为，外源性一氧化碳（COex）应用在低无毒剂量是一个潜在的 免疫治疗肺癌患者的辅助治疗。CO是由血红素内源性产生的 加氧酶-1（HO-1），在体内平衡期间起作用，将血红素分解为三种活性代谢物。我们有 证明COex以250 ppm每天施用1小时（其对应于获得的CO剂量 燃烧2支香烟）阻止肺癌和前列腺癌的进展。COex可以通过以下途径阻断肿瘤生长： 靶向癌细胞的代谢。然而，由于COex阻断不同类型肿瘤的生长， 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 合理的COex在包括免疫细胞在内的TME中具有更广泛的作用。我们的初步数据显示， COex促进更多的“免疫接受”肿瘤微环境（TME）。我们建议， TME通过调节血红素代谢调节对免疫疗法的反应。 我们的目标是： 确定COex在重定向免疫应答以增加免疫治疗功效中的作用。 具体而言，我们打算： i）确定COex和抗CTLA-4、抗PD-L1或抗PD-1治疗的组合在治疗中的有效性。 小鼠肺癌模型。 ii）确定在对免疫疗法的应答期间COex介导的经由mTOR-Notch1信号传导的CD86诱导 在肺癌模型中。 iii）定义内源性HO-1衍生的CO在对免疫疗法的应答期间的重要性。 本申请中提出的研究将描述CO和HO-1在宿主活化中的作用 通过选择性信号传导途径导致TME中骨髓功能增加的免疫应答。我们 研究结果将对肺癌患者具有根本性和治疗意义，特别是COex是 在临床试验阶段本研究与NCI的使命和RFA "NCI临床和 转化探索性/开发性研究（R21临床试验可选）"（PAR-19 - 356）。

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).