Therapeutic targeting MDSC-mediated immune suppression in cancer

针对癌症中 MDSC 介导的免疫抑制的治疗

• 批准号: 10540357
• 负责人: Valerian E Kagan
• 金额: $ 68.26万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-13 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540357
• 关键词: Address; Affect; Alcohols; Apoptosis; Arachidonate 15-Lipoxygenase; Biology; Blood; Bone Marrow; Cancer Patient; Cell Death; Cell Differentiation process; Cell physiology; Cells; Clinical; Colon Carcinoma; Cross Presentation; Data; Dendritic Cells; Down-Regulation; Generations; Glutathione; Goals; Immune; Immune response; Immunosuppression; Immunotherapy; Iron; Knowledge; Lipid Peroxidation; Lipid Peroxides; Lipids; Macrophage; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Natural Killer Cells; Necrosis; Neoplasm Metastasis; Pathologic; Patients; Peroxidases; Physiological; Population; Regulation; Role; Sampling; Signal Transduction; Spleen; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Tumor Escape; Tumor Tissue; bone circulation; clinically relevant; glutathione peroxidase; granulocyte; immunoregulation; improved; lymphoid organ; monocyte; mouse model; neutrophil; novel; novel strategies; oxidation; oxidized lipid; peripheral lymphoid organ; phospholipid-hydroperoxide glutathione peroxidase; pre-clinical; programs; repaired; therapeutic target; treatment effect; tumor; tumor microenvironment; tumor progression

Project Summary The prominent change in the myeloid compartment in cancer is the expansion of pathologically activated immature myeloid cells with the potent ability to suppress immune responses – myeloid-derived suppressor cells (MDSC). In tumor-bearing mice, the total population of MDSC consists of three groups of cells: the most abundant (>75%) immature, pathologically activated neutrophils (PMN-MDSC); less abundant (<20%) population of pathologically activated monocytes (M-MDSC); and small (<5%) population of early myeloid precursors. In the tumor microenvironment MDSC are more immunosuppressive than in peripheral lymphoid organ. However, the mechanism of this phenomenon remains rather elusive. The gaps in our knowledge is in understanding the mechanisms regulating the function of MDSC in tumors and specific requirements for their targeting. In this proposal we will test the hypothesis that there are distinct populations of MDSC in tumors. These populations can be defined by specific markers and most importantly, have different sensitivity to ferroptotic cell death which determines their functional activity. We will test the concept that targeting ferroptosis in PMN-MDSC in cancer may have functional consequences for immune responses. The goal of this project is to uncover the mechanisms regulating myeloid cell function in tumors and to develop novel approaches to the regulation of immune responses in cancer. We propose the following Specific Aims: (1) To identify the mechanism of ferroptosis-mediated immune suppression induced by PMN-MDSC in tumors; and (2) To investigate therapeutic potential of targeting ferroptosis in PMN-MDSC.

项目概要 癌症中髓样区室的显着变化是病理激活的扩张 具有抑制免疫反应的强大能力的未成熟骨髓细胞——骨髓源性抑制细胞 (MDSC) 在荷瘤小鼠中，MDSC 总数由三组细胞组成：最多 丰富 (>75%) 未成熟、病理性激活的中性粒细胞 (PMN-MDSC)；较少丰富 (<20%) 病理激活的单核细胞群 (M-MDSC) 和少量 (<5%) 早期骨髓细胞群； 在肿瘤微环境中，MDSC 比在外周淋巴中更具免疫抑制作用。 然而，这种现象的机制仍然相当难以捉摸，我们的知识还存在空白。 了解肿瘤中 MDSC 功能的调节机制及其具体要求 在本提案中，我们将检验肿瘤中存在不同 MDSC 群体的假设。 群体可以通过特定标记来定义，最重要的是，对铁死亡细胞具有不同的敏感性 我们将测试针对 PMN-MDSC 中铁死亡的概念。 该项目的目标是揭示癌症中的免疫反应。 调节肿瘤中骨髓细胞功能的机制并开发调节的新方法 癌症中的免疫反应。 我们提出以下具体目标：（1）确定铁死亡介导的免疫机制 PMN-MDSC 在肿瘤中诱导的抑制；以及 (2) 研究靶向治疗潜力 PMN-MDSC 中的铁死亡。