Modulating Th17 Cells in IDH1-Mutant Glioma to Promote Antitumor Immunity
Abstract
This proposal relates to three of Fiscal Year 2019’s Peer Reviewed Cancer Research Program Idea Award with Special Focus Topic Areas, including brain cancer, cancer in children, adolescents, and young adults, and pediatric brain cancers. At the completion of this award, we will have addressed a gap in cancer treatment that will lead to prolongment of survival that will affect the general population and the health and well-being of military Service members, Veterans, and their beneficiaries. Gliomas are a common and fatal brain tumor that tend to quickly progress to more advanced stages. Despite biological and technical advances, glioma patients continue to have a dismal prognosis with a median survival of about 15 months. While there are many reasons for the difficulties in treating this disease, one of the issues lies in that the tumors tend to be immunosuppressive and tend to protect themselves against detection from the immune system. Here, we describe the identification of mutations in IDH1 in a large set of patients with glioma. These mutations are present in nearly 80% of patients with low grade glioma and are present in nearly 100% of tumor cells. Additionally, patients with mutations in IDH1 overproduce the metabolite, D-2HG. We and others suspect that this metabolite helps the tumor cells disguise themselves against detection from the immune system and more than that, we believe it causes cells of the immune system to change on a metabolic level. The proposed studies seek to understand how D-2HG changes the cells of the immune system and whether we can reverse that effect. By reversing the effects of D-2HG, we believe that we could increase the number of one type of immune cells, the Th17 cells. We believe that by changing these cells back to their original state, that there may be the opportunity for using them to target the tumors. We suspect that with the promise of altering the immune system, that we can change the way they act and the biology of the tumor cells that they interact with. By manipulating the tumor-immune microenvironment and potentially enhancing anti-tumor immunity, we will be prolonging the otherwise dismal prognosis that many glioma patients are met with. In doing so, we will be achieving a long-term outcome pertinent to the aspirations of the Defense Health Program.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010501
Entities
People
- Christopher Pirozzi
Organizations
- Duke University
- United States Army