Modulating Th17 Cells in IDH1-Mutant Glioma to Promote Antitumor Immunity
Abstract
Gliomas are the most common primary malignant brain tumor of the central nervous system. In its most aggressive form, glioblastoma (GBM), patients are met with a dismal median survival of approximately 15 months and endure a grueling standard of care therapy. The burgeoning field of immunotherapy holds great promise with much progress being made in understanding how mutations in brain tumors impact the tumor-immune microenvironment to promote or suppress immune activity. We suspect that the most frequent mutation identified in gliomas, the R132H hotspot mutation in isocitrate dehydrogenase I (IDH1), which produces the oncometabolite D-2-hydroxyglutarate (D-2HG), profoundly alters the tumor-immune microenvironment, promoting an immunosuppressive, and thus pro-tumor milieu. We hypothesize that D-2HG alters the metabolism of the tumor infiltrating lymphocytes, skewing their differentiation and propensity for activation and response. We predict that this is mediated by mutant IDH1 and D-2HGs effects on Hif1alpha. With the promise of immunotherapy, the identification of the IDH1 mutation present in as high as 80 percent of low grade glioma patients, and the effects mutant IDH1 is having on the tumor-immune microenvironment, we suspect that we can manipulate the tumor-immune microenvironment via modulation of D-2HG, promote infiltration of various immune cells into the tumor, and promote an enduring immune response resulting in improved survival in these patients.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2022
- Accession Number
- AD1191043
Entities
People
- Christopher J. Pirozzi
Organizations
- Duke University