Immune system plays a critical role in regulation of tumor progression and profoundly influences the success or failure of cancer immune therapy. Inability of host immune system to mount potent antitumor resposnes is well established. Abnormalities in myeloid cell lineage is one of the major mechanisms of this phenomenon. In an attempt to better undertsdant the nature of these abnormalities we have focused on the role of lipid metbolism in regulation of myeloid cell function in cancer. We have recently demonstrated that DCs in cancer pateints and in tumor-bearing mice had substantially higher lipid content than their counterparts in tumor-free hosts. We have found that accumulation of lipids in DCs have profound negative implications for their ability to process and present antigens and stimulate immune responses. In this application we propose to investigate a novel concept that abnormalities in myeloid cells in cancer are caused, to a large extent, by accumulation of lipids and their subsequent peroxidation. MDSC serves as a major source of oxidized lipids (ox-lipids) in tumor microenvironment that become available for other cells including DCs. 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 ox-lipids into extracellular environment where they can be integrated into lipoproteins and picked up by DCs. Accumulation of oxidatively modified lipids by DCs dramatically affects their ability to process and present soluble proteins to T cells. If this hypothesis is correct then targeting lipid metabolism in cancer patients could represent an attractive therapeutic strategy. 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 identify the nature and the mechanisms of lipid accumulation and oxidation in myeloid cells. Using mass-spectrometry we will identify the nature of lipids accumulated in myeloid cells in cancer. We will identify the mechanism of lipid accumulation in MDSC and factors responsible for lipids oxidation in these cells.
Specific aim 2. To determine the functional consequences of lipid accumulation in myeloid cells. We will identify the role of oxidized lipids in MDSC mediated immune suppression and determine the effect of oxidized lipids on differentiation of myeloid cells. We will investigate the mechanism of abnormal antigen presentation by DCs with high lipid content.
Specific aim 3. To investigate the translational role of lipid accumulation in myeloid cells in cancer. We will study the role of lipids in the function f MDSC and DCs in cancer patients. We will evaluate the effect of therapeutic compounds targeting lipid accumulation in cells on immune responses to vaccination in tumor- bearing mice.

Public Health Relevance

In this application we propose to investigate a novel concept that abnormalities in myeloid cells in cancer are caused, to a large extent, by accumulation of lipids and their subsequent peroxidation. MDSC serves as a major source of oxidized lipids in tumor microenvironment that become available for other cells including dendritic cells. 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 environment where they can be integrated into lipoproteins and picked up by DCs. Accumulation of oxidatively modified lipids by DCs dramatically affects their ability to process and present soluble proteins to T cells. If ths hypothesis is correct then targeting lipid metabolism in cancer patients could represent an attractive therapeutic strategy. 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA165065-03
Application #
8695303
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Howcroft, Thomas K
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
$346,723
Indirect Cost
$100,936
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Tyurina, Yulia Y; Poloyac, Samuel M; Tyurin, Vladimir A et al. (2014) A mitochondrial pathway for biosynthesis of lipid mediators. Nat Chem 6:542-52
Tyurin, V A; Balasubramanian, K; Winnica, D et al. (2014) Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic 'eat-me' signals: cleavage and inhibition of phagocytosis by Lp-PLA2. Cell Death Differ 21:825-35
Mohammadyani, Dariush; Tyurin, Vladimir A; O'Brien, Matthew et al. (2014) Molecular speciation and dynamics of oxidized triacylglycerols in lipid droplets: Mass spectrometry and coarse-grained simulations. Free Radic Biol Med 76:53-60
Ramakrishnan, Rupal; Tyurin, Vladimir A; Tuyrin, Vladimir A et al. (2014) Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. J Immunol 192:2920-31