Targeting Tissue Transglutaminase to Enhance Antitumor Immunity in Ovarian Cancer
Abstract
Central Problem: Ovarian cancer tends to come back after surgery and standard chemotherapy. The recurrent tumors are generally resistant to further chemotherapy. Immunotherapy harnesses the power of the immune system to attack and eliminate cancer cells. While immunotherapy is very active in many solid tumors, its efficacy remains modest in ovarian cancer. Thus, to improve the outcomes of women afflicted with this deadly cancer, studies to understand the causes of resistance to immunotherapy and to develop new combination treatments are very much needed. Rationale: We have recently discovered a protein that promotes weakening of the immune system, which permits ovarian cancer to grow undisturbed in the peritoneal cavity. This protein, called TG2, has other well-studied functions that promote ovarian cancer growth and metastasis by directly affecting the cancer cells. We recently showed that inside immune cells, TG2 causes weakened killer T cells and active suppressive cells. We observed that blocking TG2 through genetic methods delays cancer progression. New drugs blocking TG2 are starting to be developed for use in the clinic. We reasoned that this represents an opportunity to study such drugs in combination with immunotherapy. In this project, we propose to study how TG2 interferes with the function of immune cells in animal models of ovarian cancer and in human tumor specimens. These studies will provide the foundation for new types of treatment. Research Objectives: Armed with this knowledge, we propose to figure out: (1) how the protein TG2 weakens the function of killer immune cells, (2) how do immune cells in human tumors react around cancer cells that secrete TG2? and (3) do drugs that inhibit TG2 make immunotherapy work better in ovarian cancer ? If our project is successful, we can further develop TG2 inhibitors for clinical use along with immunotherapy. Furthermore, we can start other directions of research looking at more effective ways of blocking TG2 to attack ovarian cancer cells and to augment immune responses. Relevance of the Research Project to the Mission of the OCRP: This research project is directly applicable to women with ovarian cancer, and the proposed combination treatment can make a difference in their battle with this fatal illness. Thus, the proposal fits well the mission of the OCRP to support patient-centered research to treat and cure ovarian cancer and will address fundamental biological questions related to tumor progression and development of novel therapeutics topics of high relevance to the 2022 OCRP. . New Paradigms in Ovarian Cancer: This research project proposes a new idea to explain the lack of response to immunotherapy in ovarian cancer and a new target that could be exploited to remove this natural break. The success of this project will lead to a potential intervention for women with ovarian cancer aiming to enhance the natural anti-tumor immune defense. The new therapy could help women who have failed standard chemotherapy and have limited options to extend their lives, therefore addressing a key unmet need in ovarian cancer. Research aiming to improve the outcome of fatal diseases affecting women, such as ovarian cancer, is also of particular significance to the military beneficiaries, because the number of women in the U.S. Armed Forces increased substantially from 2% in 1973 to 15% in 2002. In 2004, of 485,500 active Soldiers, 71,400 were women. Therefore, this translational project is highly significant to service members and their Families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310997
Entities
People
- Daniela E. Matei
Organizations
- Northwestern University
- United States Army