Plasma Membrane Proteins in Myeloid-Derived Suppressor Cells

描述（由申请人提供）：髓源性抑制细胞（MDSC）抑制对肿瘤生长的天然免疫应答，并阻止针对癌症的免疫治疗的临床有效性。MDSC由炎症诱导，并通过抑制肿瘤反应性T淋巴细胞的活化和通过选择巨噬细胞功能来介导其作用。这个项目将确定MDSC识别和附着在T淋巴细胞和巨噬细胞上的分子机制，并阐明炎症和癌症之间的分子联系。初步证据支持这一假设，即携带肿瘤的个体中的MDSC通过质膜受体接收促进激活和积累的信号。我们将通过鉴定潜在的受体并确定通过这些受体的激活是否增加MDSC抑制活性并促进MDSC积累和/或保留来测试这一点。将在来自植入乳腺癌的小鼠的具有低和高水平炎症的MDS细胞中定量比较蛋白质表达/丰度。将采用新技术，使质膜的分离变得容易，并广泛鉴定表面受体和其他差异表达的蛋白质。这些措施包括开发一种重金属纳米线薄膜，以简化离心分离;消除凝胶电泳与化学裂解步骤;去除双层脂质的磁性纳米管;和化学和生物信息学处理定制的中长肽含有跨膜结构域。 公共卫生相关性：最近，一个细胞家族被证明可以抑制人体对肿瘤生长的自然免疫反应，并阻止癌症免疫治疗的有效性。 该项目将确定MDS细胞识别和附着于T淋巴细胞和巨噬细胞的机制，并提供干预靶点。

DESCRIPTION (provided by applicant): Myeloid-derived suppressor cells (MDSC) suppress the natural immune-response to tumor growth, and prevent the clinical effectiveness of immunotherapy against cancer. MDSC are induced by inflammation and mediate their effects by inhibiting the activation of tumor-reactive T-lymphocytes and by co-opting macrophage function. This project will identify molecular mechanisms by which MDSC recognize and attach to T- lymphocytes and macrophages, and illuminate the molecular connection between inflammation and cancer. Preliminary evidence supports the hypothesis that MDSC in tumor-bearing individuals receive signals promoting activation and accumulation through plasma membrane receptors. We will test this by identifying potential receptors and determining if activation through these receptors increases MDSC suppressive activity, and facilitates MDSC accumulation and/or retention. Protein expression/abundance will be compared quantitatively in MDS cells with low and high levels of inflammation from mice implanted with mammary carcinomas. New technologies will be implemented to enable facile isolation of the plasma membrane and extensive identification of surface receptors and other differentially expressed proteins. These include development of a heavy metal nanowire pellicle to simplify centrifugal isolation; elimination of gel electrophoresis with a chemical cleavage step; removal of bilayer lipids by magnetic nanotubes; and chemical and bioinformatic processing customized for mid-length peptides containing trans-membrane domains. PUBLIC HEALTH RELEVANCE: Recently a family of cells has been shown to suppress the body's natural immune-response to tumor growth, and also to prevent the effectiveness of cancer immunotherapy. This project will identify the mechanisms by which MDS cells recognize and attach to T lymphocytes and macrophages, and provide targets for intervention.