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

基本信息

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
项目类别：
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

项目摘要

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.

治疗黑色素瘤患者的最新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。信息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黑色素瘤微环境。骨髓源性抑制细胞（MDSC），包括肿瘤相关中性粒细胞和肿瘤相关巨噬细胞这种免疫抑制微环境的关键驱动因素促进肿瘤生长并逃避免疫抑制免疫系统。 MDSC 鉴定的一个主要挑战是当前的表型标准使用表面标记来表征 MDSC 与用于骨髓细胞的表面标记重叠，包括中性粒细胞、巨噬细胞和单核细胞，因此区分了先天性免疫抑制子集免疫细胞将取决于功能特征。免疫抑制性质众所周知，MDSC 依赖于活性氧 (ROS)。 MDSC 呼吸爆发是主要的 ROS 的来源，主要由髓过氧化物酶 (MPO) 和 NADPH 氧化酶产生 2（氮氧化物2）。因此，MPO和NOX2可能是免疫抑制功能的重要调节因子。 MDSC。然而，人们对免疫抑制性 MDSC 的贡献知之甚少。特别是产生 MPO 和 NOX2 的 ROS 在黑色素瘤免疫治疗反应中的功能和疾病进展。该提案旨在针对 MDSC 中的呼吸爆发途径，以增强 ICT 反应并克服免疫抑制的肿瘤微环境。我们假设增加了 MPO 和 NOX2 活性有助于 MDSC 免疫抑制，其中 MPO 和 NOX2 的抑制降低 MDSC 免疫抑制功能，增强 ICT 功效。此外，MPO和NOX2 活性可能作为 MDSC 积累的新功能标志物出现，表明免疫抑制肿瘤微环境，可用作 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 MDSC 的功能是由于呼吸爆发酶 MPO 和 NOX2 的活性升高所致有助于抵抗 ICT。该提案的成功完成将确认 MPO 和 NOX2 是临床相关目标并为 MPO 和 NOX2 抑制剂的临床转化提供框架作为 ICT 的佐剂来改善治疗反应。 MPO 抑制剂 AZD5904、AZD4831 和 Verdiperstat，目前正在神经退行性疾病的临床试验中进行评估。然而，它们的影响癌症尚未被探索。这项工作将支持这些 MPO 抑制剂的重新用途增强黑色素瘤 ICT 反应的联合治疗策略。