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

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黑色素瘤微环境。骨髓来源 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目前的表型标准 使用表面标志物表征MDSC与用于骨髓细胞的重叠，包括 中性粒细胞，巨噬细胞和单核细胞，因此，区分这种先天免疫抑制亚群， 免疫细胞将依赖于功能表征。免疫抑制的性质 已知MDSC依赖于活性氧（ROS）。MDSC呼吸爆发是一种主要的 主要由髓过氧化物酶（MPO）和NADPH氧化酶产生的ROS来源 2（NOX 2）。因此，MPO和NOX 2可能是免疫抑制功能的重要调节因子。 MDSC。然而，关于免疫抑制性MDSC的贡献知之甚少， 特别是ROS产生MPO和NOX 2在黑色素瘤免疫治疗反应中的功能， 疾病进展。该提案旨在针对MDSC中的呼吸爆发途径，以增强ICT 免疫反应和克服免疫抑制肿瘤微环境。我们假设 MPO和NOX2活性有助于MDSC免疫抑制，其中MPO和NOX2活性的抑制可导致MDSC免疫抑制。 降低MDSC免疫抑制功能，增强ICT功效。此外，MPO和NOX 2 活性可能作为MDSC积累的新功能标志物出现， 免疫抑制性肿瘤微环境，并可用作ICT反应的预测标志物。 该项目旨在确定MDSC的潜在驱动因素，特别是免疫抑制剂， MDSC的功能是由于呼吸爆发酶MPO和NOX 2的活性升高， 有助于ICT抵抗。成功完成这项提案将确认MPO和NOX 2是 临床相关靶点，并为MPO和NOX 2抑制剂的临床转化提供框架 作为ICT的佐剂，以改善治疗反应。MPO抑制剂AZD 5904、AZD 4831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，它们在 癌症还没有被研究过。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。

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.