Targeting ROS enzymes in immunosuppressive myeloid cells to enhance immunotherapy

靶向免疫抑制性骨髓细胞中的 ROS 酶以增强免疫治疗

• 批准号: 10709273
• 负责人: TRACY W LIU
• 金额: $ 23.78万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709273
• 关键词: Adjuvant; Animals; Benign; Biological Assay; Bioluminescence; Blood; Blood specimen; Cell Communication; Cells; Clinical; Disease; Disease Progression; Enzyme Inhibitor Drugs; Enzymes; Evaluation; Female; Flow Cytometry; Genetic; Goals; Histamine; Histologic; Immune; Immune system; Immunosuppression; Immunotherapy; Measures; Mediating; Metastatic Melanoma; Modeling; Molecular; Mus; Myeloid Cells; Myeloid-derived suppressor cells; NADPH Oxidase; Nature; Neurodegenerative Disorders; Operative Surgical Procedures; Pathologic; Pathway interactions; Patients; Peroxidases; Phenotype; Pre-Clinical Model; Primary Neoplasm; Reactive Oxygen Species; Research Project Grants; Resected; Resistance; Respiratory Burst; Role; Sampling; Source; Surface; Time; Tissue Sample; Tissues; Translations; Treatment Efficacy; Tumor Escape; Tumor Promotion; cancer immunotherapy; cancer therapy; checkpoint therapy; enzyme activity; imaging platform; immunoregulation; improved; in vivo; inhibitor; intravital imaging; leukemia; male; melanoma; monocyte; neutrophil; novel; novel therapeutic intervention; patient subsets; pharmacologic; phase III trial; pre-clinical; preclinical study; response; success; therapy resistant; translational framework; treatment response; tumor growth; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY – Targeting ROS enzymes in immunosuppressive myeloid cells to enhance immunotherapy Although immune checkpoint therapy (ICT) has demonstrated long term survival for a subset of patients suffering from metastatic melanoma, the majority of patients do not respond. The limited success of ICT has, in large part, been due to the presence of a highly immunosuppressive tumor microenvironment. Immunosuppressive myeloid cells (IMCs) are critical drivers of this immunosuppressive microenvironment, promoting tumor growth and evasion of the immune system. A major challenge in the identification of these IMCs is that the current phenotypic criteria using surface markers to characterize them overlaps with that used for myeloid cells, including neutrophils and monocytes, thus, distinguishing this immunosuppressive subset of innate immune cells will be dependent upon functional characterization. The immunosuppressive nature of IMCs is known to depend upon reactive oxygen species (ROS). In these IMCs, the respiratory burst pathway is a major source of ROS which is primarily produced by the enzymes myeloperoxidase (MPO) and NADPH oxidase 2 (NOX2). Thus, MPO and NOX2 may be important regulators of the immunosuppressive function of IMCs. However, little is known with regards to the contribution of immunosuppressive IMCs, particularly the function of ROS producing MPO and NOX2 enzymes, in melanoma immunotherapy response and disease progression. The long-term goal of this research project is to understand the molecular mechanisms responsible for the function and accumulation of IMCs during melanoma progression. The overall objective of this proposal is to understand the contribution of the respiratory burst enzymes to the immunosuppressive function of IMCs. The central hypothesis is that increased MPO and NOX2 activity contributes to IMC immunosuppression where inhibition of these respiratory burst enzymes decreases IMC immunosuppressive function enhancing ICT efficacy and prolonging survival. The proposed aims of 1. Evaluate the contribution of respiratory burst enzymes regulating melanoma ICT response, 2. Identify IMCs interactions during melanoma ICT response, and 3. Evaluate the presence of respiratory burst enzymes pathological samples of melanoma, will be conducted using murine preclinical models and pathological samples to explore the changes in the respiratory burst enzymes. In addition, these studies will utilize specific inhibitors Verdiperstat, AZD5904 and histamine dihydrochloride for MPO and NOX2, respectively; these inhibitors are under evaluation in Phase 3 trials for neurodegenerative disorders and leukemia. We recognize these inhibitors have not yet been utilized in cancer treatments in the clinical setting; these preclinical studies will provide much needed understanding of basic mechanisms for the translation of their use with immunotherapy for cancer. These studies will be the first to characterize the role of respiratory burst enzymes in regulating immunotherapy response in metastatic melanoma.

项目总结-靶向免疫抑制髓系细胞中的ROS酶以增强 免疫疗法 尽管免疫检查点治疗(ICT)已经证明了一部分患者的长期存活 对于转移性黑色素瘤，大多数患者没有反应。信息和通信技术的有限成功在很大程度上 这是由于存在高度免疫抑制的肿瘤微环境。免疫抑制髓系 细胞(IMCs)是这种免疫抑制微环境的关键驱动力，促进肿瘤生长和 逃避免疫系统。鉴定这些IMC的一个主要挑战是，目前的表型 使用表面标记来表征它们的标准与用于包括中性粒细胞在内的髓系细胞的标准重叠 单核细胞，因此，区分这种免疫抑制的先天免疫细胞亚群将依赖于 基于功能特性。已知IMCs的免疫抑制特性依赖于反应性 氧物种(ROS)。在这些IMC中，呼吸爆发途径是ROS的主要来源，ROS主要是 由髓过氧化物酶(MPO)和NADPH氧化酶2(NOX2)产生。因此，MP0和NOX2可以 是IMCs免疫抑制功能的重要调节因子。然而，人们对此知之甚少。 免疫抑制的IMCs的作用，特别是ROS产生MPO和NOX2酶的功能， 在黑色素瘤免疫治疗反应和疾病进展方面。这项研究项目的长期目标是 了解血管内皮细胞功能和积聚的分子机制 黑色素瘤进展。这项建议的总体目标是了解呼吸系统的贡献 破裂酶对血管内皮细胞免疫抑制功能的影响。中心假设是MPO增加 而NOX2的活性有助于IMC免疫抑制，从而抑制这些呼吸爆发 酶可降低IMC的免疫抑制功能，增强ICT疗效，延长生存期。 1.评估呼吸爆发酶对黑色素瘤ICT的调节作用 反应，2.确定黑色素瘤ICT反应中IMCs的相互作用，以及3.评估 黑色素瘤的呼吸爆发酶病理样本，将使用小鼠临床前模型进行 并取病理标本，探讨呼吸爆发酶的变化。此外，这些研究将 分别用特异性抑制剂Verdiperstat、AZD5904和组胺二盐酸盐抑制MPO和NOX2； 这些抑制剂正在神经退行性疾病和白血病的3期试验中进行评估。我们 认识到这些抑制剂尚未在临床环境中用于癌症治疗；这些临床前 研究将提供急需的对基本机制的理解，以便将它们与 癌症的免疫疗法。这些研究将是第一次表征呼吸爆发酶在 调节转移性黑色素瘤的免疫治疗反应。