Multiple negative regulatory mechanisms exist that act to dampen the immune response to immune-based treatments. Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of early myeloid cells that accumulate in the blood and tumors of patients with cancer. Their numbers correlate with tumor burden and are predictive of overall survival. MDSC have been shown to reside in the peripheral blood, lymphoid tissue, and tumor tissue of mice in a number of experimental models. MDSC can inhibit the proliferation and cytotoxic activity of T cells in tumor-bearing animals through multiple mechanisms, and studies in murine models indicate that disruption of MDSC function can reverse immune tolerance to tumor antigens, stimulate anti-tumor immune responses, and induce tumor regressions. We have investigated the inhibitory effects of MDSC on human immune cells and found that they inhibit cytokine signal transduction within innate immune effector cells. Our murine experiments demonstrate that the abundant MDSC in tumor-bearing mice produce large amounts of nitric oxide which leads to increased nitration of tyrosine residues on signal transduction proteins and impaired responsiveness of immune effector cells to stimulatory signals. Also, we have recently been able to show that MDSC markedly inhibit the ability of natural killer (NK) cells to lyse monoclonal antibody (mAb)-coated tumor cells via effects on signal transduction downstream of the receptor for the constant (or

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA095426-12
Application #
8563848
Study Section
Special Emphasis Panel (ZCA1-RPRB-B)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
12
Fiscal Year
2013
Total Cost
$333,347
Indirect Cost
$94,125
Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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