Lack of B and T cell reactivity towards IDH1R132H in blood and tumor tissue from LGG patients

PurposeMutations in the isocitrate dehydrogenase-1 gene (IDH1) occur at high frequency in grade II-III gliomas (LGGs). IDH1 mutations are somatic, missense and heterozygous affecting codon 132 in the catalytic pocket of the enzyme. In LGG, most mutations (90%) result in an arginine to histidine substitution (IDH1(R132H)) providing a neo-epitope that is expressed in all tumor cells. To assess the immunogenic nature of this epitope, and its potential use to develop T cell treatments, we measured IDH1(R132H)-specific B and T cell reactivity in blood and tumor tissue of LGG patients.MethodsSera from IDH1(R132H)-mutated LGG patients (n=27) were assayed for the presence of a neo-specific antibody response using ELISA. In addition, PBMCs (n=36) and tumor-infiltrating lymphocytes (TILs, n=10) were measured for T cell activation markers and IFN-gamma production by flow cytometry and ELISA. In some assays, frequencies of CD4 T cells specific for mutated peptide presented by HLA-DR were enriched prior to T cell monitoring assays.ResultsDespite high sensitivity of our assay, we failed to detect IDH1(R132H)-specific IgG in sera of LGG patients. Similarly, we did not observe CD4 T cell reactivity towards IDH1(R132H) in blood, neither did we observe such reactivity following pre-enrichment of frequencies of IDH1(R132H)-specific CD4 T cells. Finally, we did not detect IDH1(R132H)-specific CD4 T cells among TILs.ConclusionsThe absence of both humoral and cellular responses in blood and tumors of LGG patients indicates that IDH1(R132H) is not sufficiently immunogenic and devaluates its further therapeutic exploitation, at least in the majority of LGG patients.