Lipids and Myeloid Cell Function in Cancer

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Project Summary Myeloid cells are critical component of tumor microenvironment. Under physiological conditions these cells are comprised of mature terminally differentiated cells: polymorphonuclear neutrophils (PMN) and other granulocytes; macrophages (MΦ); and dendritic cells (DCs). In cancer, myeloid compartment is dramatically affected, which is now considered as one of the major immunological hallmarks of cancer. Tumor-bearing (TB) hosts accumulate immunosuppressive MΦ, DCs in cancer are ineffective in induction of potent immune responses. 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 TB 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. The current view considers changes in myeloid cells separately. Different mechanisms applied to the different cells. The gap in our knowledge is how these different myeloid cells can interact with each other in tumor-bearing hosts. In this proposal we will test the hypothesis that oxidized lipids may provide bridge between different populations of myeloid cells in cancer and orchestrate their abnormal function. The ultimate goal of this project is not only to better understand the mechanism regulating myeloid cell function in cancer but to develop novel approaches to regulation of immune responses in cancer. To achieve this goal we propose the following specific aims: Specific aim 1. To determine the role of lectin-type oxidized LDL receptor 1 in regulation of PMN-MDSC in cancer patients Specific aim 2. To identify the role of oxidized lipids in the function of PMN-MDSC and DCs.