Myeloid-Derived Suppressor Cells Expressing Myeloperoxidase Directly Inhibit Adaptive Immune Cells Limiting Immunotherapy in Melanoma
Abstract
Skin cancer is by far the most common of all cancers, and melanoma accounts for a large majority of skin cancer-related deaths. Cancer cells have developed mechanisms to avoid destruction by our immune system. For example, the presence of immune checkpoints on cancer cells prevents recognition of cancer as harmful. A recent breakthrough in treating melanoma patients is the use of immune checkpoint therapy (ICT). ICT blocks these immune checkpoints, allowing the immune system to recognize cancer as foreign and subsequently remove it from the body. A small set of melanoma patients, after treatment with ICT, demonstrated long-term survival. Unfortunately, the majority of patients do not respond to ICT; they either never respond to treatment or develop resistance to therapy. In order to increase the number of patients that respond to ICT, more knowledge is necessary in understanding the role of the immune system during melanoma progression and ICT treatment response. Complicating matters, as cancer develops, it can also re-program the immune system to work in favor of cancer growth. One such population of immune-suppressing cells that result from melanoma is known as myeloid-derived suppressor cells (MDSCs). MDSCs are re-programmed immune cells that actively dampen the immune system from recognizing cancer while also helping cancer grow. These MDSCs have also been shown to decrease ICT treatment response in patients. This project aims to find strategies that limit the effects of MDSCs to enable successful ICT response in melanoma. Specifically, preliminary data suggests that myeloperoxidase, a major enzyme expressed in a subset of immune cells, is overexpressed in MDSCs. By hindering the function of myeloperoxidase, it is hoped that this will limit the immune suppressing effects of MDSCs or even re-program MDSCs into proper immune cells that will fight against cancer. We expect that the combination of myeloperoxidase inhibitors with ICT will increase the number of melanoma patients who respond to treatment and possibly even overcome ICT resistance. This proposal aims to understand the role of myeloperoxidase in MDSCs and how myeloperoxidase is used to inhibit other immune cells from destroying cancer. An equally if not more important goal is to demonstrate that the combination of myeloperoxidase inhibitors with ICT enhances the effectiveness of ICT in treating melanoma and hopefully overcoming treatment resistance. Funding of this project from the DoD fiscal year 2018 (FY18) Peer Reviewed Cancer Research Program career development grant would advance research in both FY18 PRCRP Topic Areas of melanoma (and other skin cancers) and immunotherapy. My ultimate career goal is to be an independent academic researcher working on critical translational questions in cancer biology and therapy. This career development grant would provide me with the support necessary to gain valuable experience and develop the skill set needed to make significant contributions to understanding and treating of melanoma. Furthermore, if awarded this career development grant, I will have an opportunity to improve my capabilities as an independent researcher. I will hone my critical thinking and conceptualization skills through supervising and conducting all aspects of this project. Successful completion of this project would continue to build upon my high-impact publication track record and provide the groundwork for a future career in understanding melanoma and enhancing immunotherapy outcome in cancer research. All aims in this project would provide knowledge regarding the biology of melanoma development, the contribution of the immune system during melanoma progression as well as the biological mechanism of ICT. Successful completion of this project (expected within the 3-year timeline of this grant) would have significant impact on melanoma patients. ICT treatment is becoming the standard of care in melanoma, therefore, by demonstrating that
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910203
Entities
People
- Tracy Liu
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army