Novel immunotherapies and cancer vaccines are being developed. The success of these therapies requires an immunocompetent host. Immune suppression occurs in many cancer patients and is a major impediment for developing successful cancer immunotherapies. Although there are numerous types of immune suppression, tumor-induced Myeloid Suppressor Cells (MSC), also known as Immature Myeloid Cells, are found in many patients and in animals with transplanted and spontaneous tumors. We have recently identified in mice a gene, the Signal Transducer and Activator of Transcription 6 (STAT6) gene, that when deleted, results in greatly improved survival and immune rejection of established metastatic mammary carcinoma following surgical removal of primary tumor. Effective tumor-immunity in post-surgery STAT6- deficient mice is mediated by three components: 1) The generation of M1 type macrophages; 2) The generation of tumor-specific CD8+ T cells; and 3) The rapid decrease to baseline in MSC levels. Because MSC accumulation and retention inhibit tumor-specific immunity and interfere with active immunotherapy, we will examine the mechanisms underlying STAT6-induced retention of MSC in tumor-bearing mice. We propose the following three Specific Aims to accomplish this goal: 1) Myeloid suppressor cells (MSC) are potent inhibitors of CD4+ and CD8+ T lymphocytes that effectively block tumor-specific immunity. We will identify the ligand/receptor combination responsible for the post-surgery retention of 4T1-induced myeloid suppressor cells. 2) We have previously shown that IFN? is required for the rapid regression of MSC in post- surgery STAT6-deficient mice. We will determine the mechanism responsible for this regression, and will clarify the role of IFN? in this process. 3) The pro-inflammatory cytokine IL-1? causes excessive accumulation and retention of MSC in post-surgery mice. We will determine how IL-1? regulates MSC levels, and ascertain if the link between inflammation and cancer is the induction of MSC. 4) MSC are found in many cancer patients and are thought to be an impediment to immune surveillance and immunotherapy. Using Gemcitabine, a drug that has recently been shown to down-regulate MSC, we will determine if reduction/elimination of MSC by itself is sufficient to mediate tumor rejection and if elimination of MSC impacts M1 macrophages and T lymphocytes. We have hypothesized that MSC block immunosurveillance, thereby facilitating the outgrowth of malignant cells. A better understanding of the regulation of tumor- induced immune suppression may reveal methods for controlling these cells in cancer patients, and thereby contribute to the development of effective cancer immunotherapies. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115880-02
Application #
7225193
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Yovandich, Jason L
Project Start
2006-04-20
Project End
2011-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
2
Fiscal Year
2007
Total Cost
$253,359
Indirect Cost
Name
University of Maryland Balt CO Campus
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
061364808
City
Baltimore
State
MD
Country
United States
Zip Code
21250
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
Ostrand-Rosenberg, Suzanne (2018) Myeloid derived-suppressor cells: their role in cancer and obesity. Curr Opin Immunol 51:68-75
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
Ostrand-Rosenberg, Suzanne (2016) Tolerance and immune suppression in the tumor microenvironment. Cell Immunol 299:23-9
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
Bronte, Vincenzo; Brandau, Sven; Chen, Shu-Hsia et al. (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150
Ku, Amy W; Muhitch, Jason B; Powers, Colin A et al. (2016) Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes. Elife 5:
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
Ostrand-Rosenberg, Suzanne; Horn, Lucas A; Alvarez, Juan A (2015) Novel strategies for inhibiting PD-1 pathway-mediated immune suppression while simultaneously delivering activating signals to tumor-reactive T cells. Cancer Immunol Immunother 64:1287-93
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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