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.
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.
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