Effects of Histone Deacetylase Inhibitors on Viability and Maturation of Tumor-Induced Myeloid-Derived Suppressor Cells
Mentor 1
Douglas A. Steeber
Location
Union 250
Start Date
24-4-2015 10:00 AM
Description
An evolving field of anti-tumor therapy is the use of drugs that alter the expression of important regulatory genes in cells, such as tumor suppressor genes. One such approach is by use of histone deacetylase (HDAC) inhibitors. Only a few of these inhibitors are currently FDA-approved for use in patients, primarily for the treatment of leukemia. While these inhibitors have shown effectiveness against blood tumors (e.g., leukemia) they have been surprisingly ineffective for the treatment of solid tumors, such as in breast cancer. Interestingly, treatment with one HDAC inhibitor was reported to increase the production of myeloid lineage cells. One such myeloid cell is the myeloid-derived suppressor cell (MDSC). These cells are immature, diverse, and rapidly expand during inflammation and pathological conditions, including cancer. In cancer patients, these cells inhibit the individual’s anti-tumor immune response, favoring the growth and spread of the tumor. Therefore, the direct anti-tumor beneficial effects of treating cancer patients with HDAC inhibitors may be masked by an increase in immunosuppressive MDSCs. Our research seeks to identify the effects of a particular HDAC inhibitor, Cpd5 (previously synthesized by the Hossain lab, Department of Chemistry, UWM) on MDSC function. Experiments will be carried out using the 4T1 mouse breast cancer model. MDSCs will be harvested from mice bearing three to four-week-old tumors. Initial in vitro experiments determined the effective dose of Cpd5 against the 4T1 tumor cells to be 10 μM. Future experiments will examine the effects of Cpd5 treatment on isolated MDSCs. Specifically, changes in activation, maturation, proliferation or immunosuppressive activity will be determined using both flow cytometry and fluorescence microscopy. The results of these experiments will provide a better understanding of the effects of HDAC inhibitors on MDSCs and may allow for development of HDAC inhibitors that do not have the undesirable effect of increasing MDSCs during cancer treatment.
Effects of Histone Deacetylase Inhibitors on Viability and Maturation of Tumor-Induced Myeloid-Derived Suppressor Cells
Union 250
An evolving field of anti-tumor therapy is the use of drugs that alter the expression of important regulatory genes in cells, such as tumor suppressor genes. One such approach is by use of histone deacetylase (HDAC) inhibitors. Only a few of these inhibitors are currently FDA-approved for use in patients, primarily for the treatment of leukemia. While these inhibitors have shown effectiveness against blood tumors (e.g., leukemia) they have been surprisingly ineffective for the treatment of solid tumors, such as in breast cancer. Interestingly, treatment with one HDAC inhibitor was reported to increase the production of myeloid lineage cells. One such myeloid cell is the myeloid-derived suppressor cell (MDSC). These cells are immature, diverse, and rapidly expand during inflammation and pathological conditions, including cancer. In cancer patients, these cells inhibit the individual’s anti-tumor immune response, favoring the growth and spread of the tumor. Therefore, the direct anti-tumor beneficial effects of treating cancer patients with HDAC inhibitors may be masked by an increase in immunosuppressive MDSCs. Our research seeks to identify the effects of a particular HDAC inhibitor, Cpd5 (previously synthesized by the Hossain lab, Department of Chemistry, UWM) on MDSC function. Experiments will be carried out using the 4T1 mouse breast cancer model. MDSCs will be harvested from mice bearing three to four-week-old tumors. Initial in vitro experiments determined the effective dose of Cpd5 against the 4T1 tumor cells to be 10 μM. Future experiments will examine the effects of Cpd5 treatment on isolated MDSCs. Specifically, changes in activation, maturation, proliferation or immunosuppressive activity will be determined using both flow cytometry and fluorescence microscopy. The results of these experiments will provide a better understanding of the effects of HDAC inhibitors on MDSCs and may allow for development of HDAC inhibitors that do not have the undesirable effect of increasing MDSCs during cancer treatment.
