Project Details
Projekt
IDH mutations in the interplay of metabolism and antileikemic immune response
Applicants
Professor Dr. Wolfgang Herr; Professorin Dr. Marina P. Kreutz, since 9/2014; Professorin Dr. Simone Thomas
Subject Area
Hematology, Oncology
Term
from 2014 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 190230491
Adoptive transfer of cytotoxic T lymphocytes (CTL) as well as vaccination with leukemia antigens are potent strategies to improve immunosurveillance against leukemias. Recently, mutations (Mut) in the genes encoding the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and 2 have been detected in acute myeloid leukemia (AML) blasts of up to 20% of patients. IDH mutations induce a neomorphic function to produce the oncometabolite 2-hydroxyglutarate (2-HG), which can alter many cellular processes upon inhibition of a-ketoglutarate dependent dioxygenases (e.g. DNA demethylases). We have previously established in vitro protocols to reliably generate leukemia reactive CD4+ and CD8+ CTL from HLA-matched naive T-cell precursors upon stimulation with patient-derived primary leukemia cells. In the submitted project we will investigate T-cell responses against IDHMut 1 and 2. For this, we will stimulate CD4+ and CD8+ T cells from AML patients and healthy donors against IDHMut proteins and predicted IDHMut peptide epitopes. To analyze the biological relevance of IDHMut specific T cells, we will adoptively transfer T-cell clones into AML engrafted immunodeficient NOD/SCID/IL2Rgcnull (NSG) mice. In the second part of the project, we will investigate the effect of 2-HG on human dendritic cells (DC) and T cells. Here, our preliminary data show that 2-HG decreases the secretion of IL-12 in DCs, which possibly impairs T-cell activation. The underlying mechanism of this effect will be further analyzed (e.g. transcriptional regulation of cytokine secretion). Our hypothesis is that IDHMut specific T cells are potent leukemia-specific effectors in adoptive immunotherapy of IDHMut + AML. Specific elimination of leukemia blasts would also reduce 2-HG levels in patients, which potentially would further strengthen antileukemia immunity.
DFG Programme
Clinical Research Units
Ehemalige Antragstellerin
Dr. Eva Gottfried, until 9/2014
