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

最近在治疗黑色素瘤患者方面的一项突破是使用免疫检查点治疗(ICT)。 不幸的是，大多数患者对信息和通信技术没有反应。信息和通信技术的有限成功在很大程度上 是由于存在高度免疫抑制的黑色素瘤微环境。髓系来源 抑制细胞(MDSCs)，包括肿瘤相关的中性粒细胞和肿瘤相关的巨噬细胞， 这种免疫抑制微环境的关键驱动因素促进了肿瘤的生长并逃避了 免疫系统。鉴定MDSCs的一个主要挑战是，目前的表型标准 使用表面标记来表征MDSCs与用于髓系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，区分这种免疫抑制亚群的先天 免疫细胞将依赖于功能特性。卡介苗的免疫抑制特性 已知MDSCs依赖于活性氧(ROS)。MDSC呼吸爆发是一种主要的 ROS的来源，主要由髓过氧化物酶(MPO)和NADPH氧化酶产生 2(NOX2)。因此，MPO和NOX2可能是机体免疫抑制功能的重要调节因子。 MDSCs。然而，关于免疫抑制MDSCs的作用知之甚少。 尤其是ROS产生MPO和NOX2，在黑色素瘤免疫治疗反应和 疾病的发展。这项建议旨在针对MDSCs中的呼吸爆发途径，以增强ICT 应对和克服免疫抑制的肿瘤微环境。我们假设增加了 MPO和NOX2活性参与MDSC免疫抑制，其中MPO和NOX2的抑制 降低MDSC的免疫抑制功能，提高ICT疗效。此外，MPO和NOX2 活性可能作为MDSC积聚的新功能标志物出现，表明 免疫抑制肿瘤微环境，可作为ICT反应的预测标记物。 该项目旨在确定MDSCs的潜在驱动因素，具体地说，免疫抑制 MDSCs的功能是由于呼吸爆发酶MPO和NOX2活性升高所致 助长了信息和通信技术的阻力。成功完成该提案将确认MPO和NOX2是 临床相关靶点并为MPO和NOX2抑制剂的临床翻译提供框架 作为ICT的佐剂，以提高治疗反应。MPO抑制剂，AZD5904，AZD4831和Verdiperstat， 目前正在对神经退行性疾病的临床试验进行评估。然而，它们在 癌症还没有被研究过。这项工作将支持将这些MPO抑制剂作为一种 联合治疗策略以增强对黑色素瘤的ICT反应。

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.