Targeting Repetitive Elements to Reverse Immune Evasion in Ovarian Cancer
Abstract
In 2018, over 14,000 women in the United States died of ovarian cancer (OC). While conventional chemotherapy can result in temporary remission, there are few therapies that offer long-term remission or cure. Therapies that activate the body’s own immune cells to seek and destroy cancer cells have shown great promise in many tumor types. However, most OC patients do not respond to immunotherapy because the immune cells of the body do not recognize the tumors as being foreign. If we can make the immune cells “see” the tumor cells, we believe patients are more likely to respond to immune therapy. On way to do this is to make the tumor cells show new markers, so called “neoantigens,” on their surface. Immune cells will recognize these neoantigens as being foreign and thus target and kill the cancer cell. Unfortunately, OC cells rarely express these neoantigens, allowing them to hide from the immune system. We have shown that treating tumors with drugs that unveil new antigens, by removing DNA methylation, increases immune cell activity against OC. DNA methylation is a chemical “tag” placed on a strand of DNA that prevents the DNA from eventually being made into a protein. When DNA methylation of specific regions of DNA called repetitive elements (REs) is blocked, the cancer cell acts as if it is infected by a virus. The body’s immune system responds with what is known as the interferon response (IR). The IR recruits and activates immune cells to the tumors and the immune cells ultimately destroy the cancer cells. However, many questions remain to be answered about this process. We do not yet know (1) how the immune cells are attracted to the tumor by IR and (2) whether blocking DNA methylation allows REs to serve as “neoantigens” by the tumors to activate the body’s immune cells. Our central hypothesis is that RE expression in OC tumors, by presenting as neoantigens, will cause a viral alarm response and allow the body’s immune system to seek and destroy the tumor cells. The goals of this proposal are to further understand RE interactions with the patient’s immune system so that we can use drugs like DNA methylation inhibitors in combination with host immune cells targeting REs as neoantigens on cancer cells. We will do this by (1) determining how inhibiting DNA methylation changes signaling from tumor cells to activate host immune cells and (2) determining whether host immune cells that recognize RE proteins can specifically kill OC cells. My commitment to a career in OC research is unwavering because, despite decades of research, advanced OC remains a fatal disease. My long-term goal is to become a leader in the OC field in the areas of epigenetics and immunology and, with my clinical partners, to run clinical trials of novel therapeutic combinations to eradicate this disease. I have extensive expertise in cancer epigenetics and regulation of REs and have training in tumor immunology. This award will allow me to perform the experiments proposed in this grant and learn new skills from my primary mentor, Dr. Daniel Powell (University of Pennsylvania), who has extensive experience in T cell biology and OC immunology. I will learn new immunobiology from my other mentor, Dr. Catherine Bollard, on site at George Washington University. Dr. Bollard is a world-renowned cancer immunologist with expertise in T cell biology and has ongoing collaborations and grant applications with me. I am applying for the OCA to learn new techniques and obtain additional training that will significantly enhance and sustain my career. Together with my mentors I have designed a comprehensive career development plan that addresses both scientific and career training to allow me to be at the forefront of OC research. I look forward to participating in the OC Academy and bringing my expertise in repetitive element biology and epigenetic regulation to the team. Translationally, this research has the potential to identify new and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010273
Entities
People
- Katherine Chiappinelli
Organizations
- George Washington University
- United States Army