Therapeutic targeting MDSC-mediated immune suppression in cancer

项目摘要 癌症中髓样区室的显著变化是病理激活的 具有有效抑制免疫反应能力的未成熟骨髓细胞-骨髓来源的抑制细胞 （MDSC）。在荷瘤小鼠中，MDSC的总群体由三组细胞组成： 丰富（>75%）未成熟的病理活化中性粒细胞（PMN-MDSC）;不太丰富（<20%） 病理活化单核细胞（M-MDSC）群体;和早期髓系造血干细胞（<5%）群体 前体在肿瘤微环境中，MDSC比外周淋巴细胞更具有免疫抑制作用。 器官.然而，这一现象的机制仍然相当难以捉摸。我们知识的差距在于 了解MDSC在肿瘤中的功能调节机制及其对MDSC的特殊要求， 面向.在这个提议中，我们将检验肿瘤中存在不同MDSC群体的假设。这些 群体可以通过特定的标记物来定义，最重要的是，对铁凋亡细胞具有不同的敏感性。 死亡决定了它们的功能活动。我们将测试在PMN-MDSC中靶向铁凋亡的概念， 可能会对免疫反应产生功能性影响。这个项目的目标是揭示 调节肿瘤中骨髓细胞功能的机制，并开发新的方法来调节肿瘤中骨髓细胞的功能。 癌症的免疫反应 本研究的具体目的如下：（1）探讨铁中毒介导的免疫机制 PMN-MDSC在肿瘤中诱导的抑制作用;（2）研究靶向治疗的潜力 PMN-MDSC中的铁凋亡。

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.