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

ABSTRACT:

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-? 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.

SUBMITTER: Weenink B 

PROVIDER: S-EPMC6660510 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature