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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM021248-34
Application #
8197522
Study Section
Enabling Bioanalytical and Biophysical Technologies Study Section (EBT)
Program Officer
Edmonds, Charles G
Project Start
1987-07-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
34
Fiscal Year
2012
Total Cost
$361,776
Indirect Cost
$86,025
Name
University of Maryland College Park
Department
Chemistry
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Lee, Amanda E; Geis-Asteggiante, Lucia; Dixon, Emma K et al. (2016) Preparing to read the ubiquitin code: characterization of ubiquitin trimers by top-down mass spectrometry. J Mass Spectrom 51:315-21
Beury, Daniel W; Carter, Kayla A; Nelson, Cassandra et al. (2016) Myeloid-Derived Suppressor Cell Survival and Function Are Regulated by the Transcription Factor Nrf2. J Immunol 196:3470-8
Kim, Yeji; Edwards, Nathan; Fenselau, Catherine (2016) Extracellular vesicle proteomes reflect developmental phases of Bacillus subtilis. Clin Proteomics 13:6
Ostrand-Rosenberg, Suzanne (2016) Tolerance and immune suppression in the tumor microenvironment. Cell Immunol 299:23-9
Castañeda, Carlos A; Dixon, Emma K; Walker, Olivier et al. (2016) Linkage via K27 Bestows Ubiquitin Chains with Unique Properties among Polyubiquitins. Structure 24:423-36
Bronte, Vincenzo; Brandau, Sven; Chen, Shu-Hsia et al. (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150
Parker, Katherine H; Horn, Lucas A; Ostrand-Rosenberg, Suzanne (2016) High-mobility group box protein 1 promotes the survival of myeloid-derived suppressor cells by inducing autophagy. J Leukoc Biol 100:463-70
Burke, Meghan C; Wang, Yan; Lee, Amanda E et al. (2015) Unexpected trypsin cleavage at ubiquitinated lysines. Anal Chem 87:8144-8
Shah, Swati; Cannon, Joe R; Fenselau, Catherine et al. (2015) A Duplicated ESAT-6 Region of ESX-5 Is Involved in Protein Export and Virulence of Mycobacteria. Infect Immun 83:4349-61
Parker, Katherine H; Beury, Daniel W; Ostrand-Rosenberg, Suzanne (2015) Myeloid-Derived Suppressor Cells: Critical Cells Driving Immune Suppression in the Tumor Microenvironment. Adv Cancer Res 128:95-139

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