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 #
3R01GM021248-33S1
Application #
8214747
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
2010-12-01
Budget End
2011-11-30
Support Year
33
Fiscal Year
2011
Total Cost
$69,307
Indirect Cost
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
Ostrand-Rosenberg, Suzanne (2018) Myeloid derived-suppressor cells: their role in cancer and obesity. Curr Opin Immunol 51:68-75
Adams, Katherine R; Chauhan, Sitara; Patel, Divya B et al. (2018) Ubiquitin Conjugation Probed by Inflammation in Myeloid-Derived Suppressor Cell Extracellular Vesicles. J Proteome Res 17:315-324
Chen, Dapeng; Gomes, Fabio; Abeykoon, Dulith et al. (2018) Top-Down Analysis of Branched Proteins Using Mass Spectrometry. Anal Chem 90:4032-4038
Geis-Asteggiante, LucĂ­a; Belew, Ashton T; Clements, Virginia K et al. (2018) Differential Content of Proteins, mRNAs, and miRNAs Suggests that MDSC and Their Exosomes May Mediate Distinct Immune Suppressive Functions. J Proteome Res 17:486-498
Horn, Lucas A; Long, Tiha M; Atkinson, Ryan et al. (2018) Soluble CD80 Protein Delays Tumor Growth and Promotes Tumor-Infiltrating Lymphocytes. Cancer Immunol Res 6:59-68
Rose, Rebecca L; Choksawangkarn, Waeowalee; Fenselau, Catherine (2018) Application of Higher Density Iron Oxide Nanoparticle Pellicles to Enrich the Plasma Membrane and Its Proteome from Cells in Suspension. Methods Mol Biol 1722:79-90
Ostrand-Rosenberg, Suzanne; Fenselau, Catherine (2018) Myeloid-Derived Suppressor Cells: Immune-Suppressive Cells That Impair Antitumor Immunity and Are Sculpted by Their Environment. J Immunol 200:422-431
Aebersold, Ruedi; Agar, Jeffrey N; Amster, I Jonathan et al. (2018) How many human proteoforms are there? Nat Chem Biol 14:206-214
Singh, Rajesh K; Kazansky, Yaniv; Wathieu, Donald et al. (2017) Hydrophobic Patch of Ubiquitin is Important for its Optimal Activation by Ubiquitin Activating Enzyme E1. Anal Chem 89:7852-7860
Chauhan, Sitara; Danielson, Steven; Clements, Virginia et al. (2017) Surface Glycoproteins of Exosomes Shed by Myeloid-Derived Suppressor Cells Contribute to Function. J Proteome Res 16:238-246

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