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 (M?); 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 M?, 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.

Public Health Relevance

In this application we propose to investigate the role of oxidized lipids in regulation of function of myeloid cells in cancer. We propose that lipids accumulated in MDSC are quickly and massively oxidized and then contribute to immune suppressive activity of these cells during close contact with T cells, interfere with MDSC differentiation to mature myeloid cells and promote their apoptosis. Dying MDSC release large quantities of oxidized lipids into extracellular space where they can be picked up by DCs and macrophages and block DC ability to cross-present antigens and polarize macrophages to immune suppressive cells. Targeting lipid metabolism with specific inhibitors proposed in this application could represent an attractive therapeutic strategy in cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA165065-07
Application #
9739308
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Kuo, Lillian S
Project Start
2012-09-01
Project End
2023-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Chao, Honglu; Anthonymuthu, Tamil S; Kenny, Elizabeth M et al. (2018) Disentangling oxidation/hydrolysis reactions of brain mitochondrial cardiolipins in pathogenesis of traumatic injury. JCI Insight 3:
Anthonymuthu, Tamil S; Kenny, Elizabeth M; Lamade, Andrew M et al. (2018) Oxidized phospholipid signaling in traumatic brain injury. Free Radic Biol Med 124:493-503
Hassannia, Behrouz; Wiernicki, Bartosz; Ingold, Irina et al. (2018) Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J Clin Invest 128:3341-3355
Gaschler, Michael M; Andia, Alexander A; Liu, Hengrui et al. (2018) FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol 14:507-515
He, Yu-Mei; Li, Xing; Perego, Michela et al. (2018) Transitory presence of myeloid-derived suppressor cells in neonates is critical for control of inflammation. Nat Med 24:224-231
Veglia, Filippo; Tyurin, Vladimir A; Mohammadyani, Dariush et al. (2017) Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer. Nat Commun 8:2122
Gabrilovich, Dmitry I (2017) Myeloid-Derived Suppressor Cells. Cancer Immunol Res 5:3-8
Tyurina, Yulia Y; Lou, Wenjia; Qu, Feng et al. (2017) Lipidomics Characterization of Biosynthetic and Remodeling Pathways of Cardiolipins in Genetically and Nutritionally Manipulated Yeast Cells. ACS Chem Biol 12:265-281
Kagan, Valerian E; Bay?r, Hülya; Tyurina, Yulia Y et al. (2017) Elimination of the unnecessary: Intra- and extracellular signaling by anionic phospholipids. Biochem Biophys Res Commun 482:482-490
Veglia, Filippo; Gabrilovich, Dmitry I (2017) Dendritic cells in cancer: the role revisited. Curr Opin Immunol 45:43-51

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