Targeting Myeloid Derived Suppressor Cells (MDSC) Using a Novel Adenosine Monophosphate-activated Protein Kinase (AMPK) Activator: OSU-53.
Loading...
Date
2015-05
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
The Ohio State University
Abstract
The tumor microenvironment (TME) is composed of many different cell types including immune cells. Myeloid cells such as tumor associated macrophages (TAM) and myeloid derived suppressor cells (MDSC) comprise a significant portion of the immune cells that are recruited to the tumor site. Immune cells promote tumor growth through two opposing mechanisms. TAMs secrete cytokines and proteases that facilitate tumor growth and angiogenesis. In contrast, MDSC promote tumor growth by suppressing the function of normal immune cells. MDSC are primarily immunosuppressive in nature and expand in number in tumor-bearing hosts due to tumor-secreted factors. MDSC are recruited into tumor stroma from bone marrow, blood and adjacent tissue. MDSC can suppress NK and T cell functions via a variety of mechanisms. This involves the generation of reactive oxygen species (ROS), nitric oxide (NO), the release of arginase and the production of cytokines. The presence of MDSC in the TME can interfere with immune-based therapy and strategies aimed at eliminating MDSC from the TME can increase the efficacy of these treatments. This study investigated whether treatment of MDSC with OSU-53, a compound that was designed inhibit the enzyme known as 5' AMP-activated protein kinase (AMPK) can affect MDSC function. A murine MDSC cell line, MSC-2, was used for in vitro experiments. OSU-53 at concentrations of 0.5-5 uM did not induce apoptosis in this cell line. Treatment of MSC-2 with OSU-53 reduced their production of NO by 1.5 fold. There was also a 2-fold decrease in the migration of MSC-2 cells in response to tumor cells (p<0.001). In summary, OSU-53 can affect MDSC function in vitro. Future studies will be aimed at investigating whether OSU-53 can inhibit MDSC function in tumor-bearing mice receiving antibody treatments.
Description
Keywords
Cancer, Immunology, Myeloid derived suppressor cells, OSU-53