Targeting ROS enzymes in myeloid-derived suppressor cell to enhance immunotherapy

靶向骨髓源性抑制细胞中的 ROS 酶以增强免疫治疗

• 批准号: 10620610
• 负责人: TRACY W LIU
• 金额: $ 26.37万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620610
• 关键词: Adjuvant; Animals; Biological Assay; Blood specimen; Cell Communication; Cell Separation; Cells; Clinic; Clinical; Clinical Trials; Data; Dependence; Disease Progression; Dissection; Enzymes; Genetic; Goals; Histology; Immune; Immune Cell Suppression; Immune system; Immunologic Adjuvants; Immunosuppression; Immunotherapy; Malignant Neoplasms; Modeling; Molecular; Myeloid Cells; Myeloid-derived suppressor cells; NADPH Oxidase; Nature; Neurodegenerative Disorders; Pathway interactions; Patients; Peroxidases; Pharmacology; Phenotype; Reactive Oxygen Species; Research Project Grants; Resistance; Respiratory Burst; Sampling; Skin; Source; Surface; Therapeutic; Tissues; Translating; Treatment Efficacy; Tumor-associated macrophages; Work; checkpoint therapy; clinical translation; clinically relevant; improved; in vivo imaging; inhibitor; macrophage; melanoma; migration; molecular imaging; monocyte; neutrophil; novel; predictive marker; recruit; responders and non-responders; response; success; treatment response; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions; Adjuvant; Animals; Biological Assay; Blood specimen; Cell Communication; Cell Separation; Cells; Clinic; Clinical; Clinical Trials; Data; Dependence; Disease Progression; Dissection; Enzymes; Genetic; Goals; Histology; Immune; Immune Cell Suppression; Immune system; Immunologic Adjuvants; Immunosuppression; Immunotherapy; Malignant Neoplasms; Modeling; Molecular; Myeloid Cells; Myeloid-derived suppressor cells; NADPH Oxidase; Nature; Neurodegenerative Disorders; Pathway interactions; Patients; Peroxidases; Pharmacology; Phenotype; Reactive Oxygen Species; Research Project Grants; Resistance; Respiratory Burst; Sampling; Skin; Source; Surface; Therapeutic; Tissues; Translating; Treatment Efficacy; Tumor-associated macrophages; Work; checkpoint therapy; clinical translation; clinically relevant; improved; in vivo imaging; inhibitor; macrophage; melanoma; migration; molecular imaging; monocyte; neutrophil; novel; predictive marker; recruit; responders and non-responders; response; success; treatment response; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

A recent breakthrough in treating melanoma patients is the use of immune checkpoint therapy (ICT). Unfortunately, the majority of patients do not respond to ICT. The limited success of ICT has, in large part, been due to the presence of a highly immunosuppressive melanoma microenvironment. Myeloid-derived suppressor cells (MDSCs), including tumor-associated neutrophils and tumor-associated macrophages, are critical drivers of this immunosuppressive microenvironment which promote tumor growth and evade the immune system. A major challenge in the identification of MDSCs is that the current phenotypic criteria using surface markers to characterize MDSCs overlaps with that used for myeloid cells, including neutrophils, macrophages and monocytes, thus, distinguishing this immunosuppressive subset of innate immune cells will be dependent upon functional characterization. The immunosuppressive nature of MDSCs are known to depend upon reactive oxygen species (ROS). MDSC respiratory burst 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 MDSCs. However, little is known with regards to the contribution of immunosuppressive MDSCs, particularly the function of ROS producing MPO and NOX2, in melanoma immunotherapy response and disease progression. This proposal aims to target the respiratory burst pathway in MDSCs to enhance ICT response and overcome the immunosuppressive tumor microenvironment. We hypothesize that increased MPO and NOX2 activity contributes to MDSC immunosuppression where the inhibition of MPO and NOX2 decreases MDSC immunosuppressive function enhancing ICT efficacy. In addition, MPO and NOX2 activity may emerge as novel functional markers of MDSC accumulation indicative of an immunosuppressive tumor microenvironment, and may be used as a predictive marker for ICT response. This project aims to identify the underlying drivers of MDSCs, specifically, that the immunosuppressive function of MDSCs is due to the elevated activity of the respiratory burst enzymes MPO and NOX2 which contribute to ICT resistance. Successful completion of this proposal would confirm that MPO and NOX2 are clinically-relevant targets and provide the framework for the clinical translation of MPO and NOX2 inhibitors as adjuvants for ICT to improve treatment response. MPO inhibitors, AZD5904, AZD4831 and Verdiperstat, are currently being evaluated in clinical trials for neurodegenerative disease. However, their effects in cancer have not been explored. This work would support the repurposed use of these MPO inhibitors as a combination therapeutic strategy to enhance ICT response in melanoma.

最近在治疗黑色素瘤患者方面的突破是使用免疫检查点疗法（ICT）。 不幸的是，大多数患者对ICT没有反应。 ICT的成功很大，在很大程度上是 由于存在高度免疫抑制性黑色素瘤微环境。髓样衍生 抑制细胞（MDSC），包括肿瘤相关的中性粒细胞和与肿瘤相关的巨噬细胞 这种免疫抑制性微环境的关键驱动因素促进肿瘤生长并逃避 免疫系统。 MDSC识别的主要挑战是当前的表型标准 使用表面标记来表征MDSC与用于髓样细胞的重叠，包括 中性粒细胞，巨噬细胞和单核细胞，因此区分了这种免疫抑制作用 免疫细胞将取决于功能表征。免疫抑制性质 已知MDSC取决于活性氧（ROS）。 MDSC呼吸爆发是主要的 ROS的来源主要由酶，髓过氧化物酶（MPO）和NADPH氧化酶产生 2（NOX2）。因此，MPO和NOX2可能是免疫抑制功能的重要调节剂 MDSCS。但是，关于免疫抑制MDSC的贡献，知之甚少 特别是产生MPO和NOX2的ROS的功能，在黑色素瘤免疫疗法反应中以及 疾病进展。该提案旨在针对MDSC的呼吸道爆发途径以增强ICT 反应并克服免疫抑制性肿瘤微环境。我们假设增加了 MPO和NOX2活性有助于MDSC免疫抑制，其中抑制MPO和NOX2 降低MDSC免疫抑制功能，从而提高ICT效力。此外，MPO和NOX2 活性可能是MDSC积累的新功能标志物，指示 免疫抑制性肿瘤微环境，可以用作ICT反应的预测标记。 该项目旨在确定MDSC的潜在驱动因素，特别是免疫抑制作用 MDSC的功能是由于呼吸爆发酶MPO和NOX2的活性升高。 有助于ICT抗性。该提案的成功完成将确认MPO和NOX2是 与临床相关的目标，并为MPO和NOX2抑制剂的临床翻译提供框架 作为ICT改善治疗反应的佐剂。 MPO抑制剂，AZD5904，AZD4831和Verdiperstat， 目前正在临床试验中评估神经退行性疾病。但是，它们在 癌症尚未探索。这项工作将支持将这些MPO抑制剂作为一个重新利用 结合治疗策略以增强黑色素瘤的ICT反应。