Interferon Epsilon: A New Localized Immunotherapy for Ovarian Cancer
Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most prevalent and deadly form of ovarian cancer. Most patients are diagnosed late in the course of disease development, with advanced disease that has spread beyond the original site into the peritoneal cavity. The standard treatment is surgery to remove most of the visible tumor plus chemotherapy, or targeted therapies known as PARP inhibitors, to kill residual tumor cells. However, most (90%) of those women receiving chemotherapy eventually develop resistance to the treatment, and PARP inhibitors are only effective for a subset of tumors. Therefore, survival rates for patients with HGSOC are very low, and it is important to develop new therapies that can treat this disease. A new type of cancer therapy is immunotherapies, which target the body’s immune system to improve its ability to fight the tumor. Cancer immunotherapies have been very successful in the treatment of other types of cancer, but they have had limited success in ovarian cancer. This is in part because HGSOC tumors recruit and activate immunosuppressive cells that prevent anti-tumor immune cells from killing tumor cells, and promote tumor growth. Therefore, there is a critical need to develop new therapeutics which can reverse this immunosuppressive environment in HGSOC and improve patient survival. Interferons (IFN) are a type of signaling protein, or cytokine, that can kill tumor cells and activate anti- tumor immune responses. We discovered a new IFN, called IFN epsilon, which is found in the female reproductive tract where it protects against infection. In a previous project, funded by a U.S. DOD Pilot Award, we performed studies in mice and found that IFN epsilon also protects against ovarian cancer. Since then, we have performed follow-up mouse studies that revealed that IFN epsilon controls ovarian cancer progression through its activities on immune cells, not tumor cells. Importantly, IFN epsilon significantly reduced the numbers and activation of immunosuppressive immune cells in the peritoneal cavity and activated anti-tumor immune cells. Based on these exciting and very promising results, we are now well placed to begin a new study to understand which immune cells are important to the anti-tumor activity of IFN epsilon and to test whether it is effective on human cells. As the discoverers of this protein, we are in a unique position to fully study its role on immune cells in ovarian cancer and determine whether we can use it as a new therapy in the future. In this project, we plan to characterize the immune response to IFN epsilon in the peritoneal cavity and determine which cell types are the main targets of IFN epsilon in ovarian cancer. These studies will be performed in mice, which will allow us to experiment with different immune cell populations in ways that are not possible in humans. We will complement our mouse studies through analysis of IFN epsilon activity on human peritoneal immune and tumor cells that are isolated from ascites fluids from ovarian cancer patients; these ascites are ordinarily drained to reduce patient discomfort and are otherwise discarded. We will also create a new mouse model of ovarian cancer that allows us to test the effects of IFN epsilon therapy on human peritoneal cells. In our studies, we will use powerful technologies that allow us to measure the expression of different genes and proteins at the level of a single cell, allowing us to compare the responses to IFN epsilon observed in mouse and human cells. This research will generate new knowledge that will increase our understanding of how IFN epsilon works to protect against ovarian cancer and provide important preclinical data to support first-in-human clinical trials, ultimately enabling development of IFN epsilon as a new immunotherapy for ovarian cancer. We will also make all of our data and new mouse model publicly available to other researchers to support their work in id
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310268
Entities
People
- Nicole Campbell
Organizations
- Monash University
- United States Army