Targeting ROS enzymes in immunosuppressive myeloid cells to enhance immunotherapy

项目总结-靶向免疫抑制骨髓细胞中的ROS酶，以增强 免疫治疗 尽管免疫检查点疗法（ICT）已经证明了患有免疫缺陷综合征的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。免疫抑制髓样 细胞（IMC）是这种免疫抑制微环境的关键驱动因素，促进肿瘤生长， 免疫系统的逃避。鉴定这些IMC的一个主要挑战是目前的表型 使用表面标记物来表征它们的标准与用于骨髓细胞（包括中性粒细胞）的标准重叠 因此，区分这种先天免疫细胞的免疫抑制亚群将依赖于 功能特性。已知IMC的免疫抑制性质依赖于反应性免疫抑制。 氧物种（ROS）。在这些IMC中，呼吸爆发途径是ROS的主要来源， 由髓过氧化物酶（MPO）和NADPH氧化酶2（NOX 2）产生。因此，MPO和NOX 2可以 是IMC免疫抑制功能的重要调节剂。然而，关于这一点知之甚少。 免疫抑制性IMC的贡献，特别是ROS产生MPO和NOX 2酶的功能， 在黑色素瘤免疫治疗反应和疾病进展中的作用。该研究项目的长期目标是 为了了解负责IMC功能和积累的分子机制， 黑素瘤进展。本提案的总体目标是了解呼吸系统的贡献， 爆发酶的免疫抑制功能的IMC。核心假设是MPO增加 和NOX 2活性有助于IMC免疫抑制，其中抑制这些呼吸爆发 酶降低IMC免疫抑制功能，增强ICT功效并延长存活。 提出的目标1。评价呼吸爆发酶调节黑色素瘤ICT的作用 响应，2.确定黑色素瘤ICT反应过程中IMC的相互作用，以及3.评价是否存在 呼吸爆发酶黑色素瘤病理样本，将使用鼠临床前模型进行 和病理标本，探讨呼吸爆发酶的变化。此外，这些研究将 分别利用MPO和NOX 2的特异性抑制剂Verdiperstat、AZD 5904和二盐酸组胺; 这些抑制剂正在神经变性疾病和白血病的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 研究将提供急需的基本机制的理解，以翻译他们的使用， 癌症的免疫疗法。这些研究将首次描述呼吸爆发酶在 调节转移性黑色素瘤的免疫治疗反应。

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.