Therapeutic targeting MDSC-mediated immune suppression in cancer

项目摘要 在癌症中，髓系室的显著变化是病理激活的 具有强大免疫抑制能力的未成熟髓系细胞-髓系来源的抑制细胞 (MDSC)。在荷瘤小鼠中，MDSC的总群体由三组细胞组成：最多的 大量(&gt；75%)未成熟的、病理激活的中性粒细胞(PMN-MDSC)；较少的(&lt；20%) 病理激活的单核细胞(M-MDSC)群体；以及少量(5%)的早期髓系细胞 先驱物。在肿瘤微环境中，MDSC比外周淋巴组织更具免疫抑制作用 管风琴。然而，这种现象的机制仍然相当难以捉摸。我们知识上的差距在于 了解肿瘤中多药耐药干细胞功能的调节机制及其对其的特殊要求 瞄准目标。在这项建议中，我们将检验假设，即肿瘤中存在不同的MDSC群体。这些 群体可以由特定的标记来定义，最重要的是，对铁链细胞具有不同的敏感性 死亡决定了它们的功能活动。我们将在PMN-MDSC中测试靶向下垂的概念 在癌症中可能对免疫反应产生功能影响。这个项目的目标是揭开 调节肿瘤髓系细胞功能的机制和开发新的调节方法 癌症中的免疫反应。 我们提出了以下具体目标：(1)确定铁下垂介导的免疫机制 PMN-MDSC对肿瘤的抑制作用；(2)研究靶向治疗的可能性 PMN-MDSC的铁性下垂。

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.