Identification of CRKII, CFL1, CNTN1, NME2, and TKT as Novel and Frequent T-cell Targets in Human IDH-Mutant Glioma.

Identification of CRKII, CFL1, CNTN1, NME2, and TKT as Novel and Frequent T-cell Targets in Human IDH-Mutant Glioma.

Clin Cancer Res. 2018 Mar 21;:

Authors: Dettling S, Stamova S, Warta R, Schnölzer M, Rapp C, Rathinasamy A, Reuss D, Pocha K, Roesch S, Jungk C, Warnken U, Eckstein V, Grabe N, Schramm C, Weigand MA, von Deimling A, Unterberg A, Beckhove P, Herold-Mende C

Abstract
PURPOSE: Successful immunotherapies for IDH mut gliomas require better knowledge of T-cell target antigens. Here, we elucidated their antigen repertoire recognized by spontaneous T-cell responses using an unbiased proteomic approach.
EXPERIMENTAL DESIGN: Protein fractionations of tissue lysates from IDH mut gliomas (n=4) were performed. Fractions were tested by IFN-ᵯE; ELISpot assay for recognition through patient's T-cells. Proteins of immunogenic fractions were identified by mass spectrometry and validated by in silico-predicted synthetic long-peptides in patients of origin, additional IDH mut glioma patients (n=16), and healthy donors (n=13). mRNA and protein expression of immunogenic antigens was analyzed in tumor tissues and IDH mut glioma stem-like cells (GSCs). HLA-A*02-restricted T-cell epitopes were functionally determined by short peptides and numbers of antigen-specific T-cells by HLA-peptide tetramer analysis.
RESULTS: 2,897 proteins were identified in immunogenic tumor fractions. Based on a thorough filter process 79 proteins were selected as potential T-cell antigens. 26 of these were recognized by the patients' T-cells and five of them (CRKII, CFL1, CNTN1, NME2, and TKT) in up to 56% unrelated IDH mut glioma patients. Most immunogenic tumor-associated antigens (TAAs) were expressed in IDH mut gliomas and GSCs, while being almost absent in normal brain tissues. Finally, we identified HLA-A*02-restricted epitopes for CRKII, NME2, and TKT that were recognized by up to 2.82% of antigen-specific peripheral cytotoxic T-cells in IDH mut glioma patients.
CONCLUSION: By analyzing the repertoire of T-cell target antigens in IDH mut glioma patients, we identified five novel immunogenic TAAs and confirmed their expression on IDH mut tumors and GSCs.

PMID: 29563135 [PubMed - as supplied by publisher]

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