Lack of B and T cell reactivity towards IDH1 R132H in blood and tumor tissue from LGG patients.

Purpose: Mutations 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.
Methods: Sera 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-γ 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.
Results: Despite 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.
Conclusions: The 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.