Identification of CRKII, CFL1, CNTN1, NME2, and TKT as novel and frequent T-cell targets in human IDH-mutant glioma
Dettling S, Stamova S, Warta R, Schnoelzer 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 (2018)
Publication Type: Journal article
Publication year: 2018
Journal
Book Volume: 24
Pages Range: 2951-2962
Journal Issue: 12
DOI: 10.1158/1078-0432.CCR-17-1839
Abstract
Purpose: Successful immunotherapies for IDHmut 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 IDHmut gliomas (n ¼ 4) were performed. Fractions were tested by IFNg ELISpot assay for recognition through patients' 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 IDHmut glioma patients (n ¼ 16), and healthy donors (n ¼ 13). mRNA and protein expression of immunogenic antigens was analyzed in tumor tissues and IDHmut glioma stem-like cells (GSC). HLA-A02–restricted T-cell epitopes were functionally determined by short peptides and numbers of antigen-specific T cells by HLA-peptide tetramer analysis. Results: A total of 2,897 proteins were identified in immunogenic tumor fractions. Based on a thorough filter process, 79 proteins were selected as potential T-cell antigens. Twenty-six of these were recognized by the patients' T cells, and five of them (CRKII, CFL1, CNTN1, NME2, and TKT) in up to 56% unrelated IDHmut glioma patients. Most immunogenic tumor-associated antigens (TAA) were expressed in IDHmut gliomas and GSCs, while being almost absent in normal brain tissues. Finally, we identified HLA-A02–restricted epitopes for CRKII, NME2, and TKT that were recognized by up to 2.82% of antigen-specific peripheral cytotoxic T cells in IDHmut glioma patients. Conclusions: By analyzing the repertoire of T-cell target antigens in IDHmut glioma patients, we identified five novel immunogenic TAAs and confirmed their expression on IDHmut tumors and GSCs.
Involved external institutions
Universitätsklinikum Heidelberg
Germany (DE)
Regensburg Center for Interventional Immunology
Germany (DE)
Deutsches Krebsforschungszentrum (DKFZ)
Germany (DE)
Ruprecht-Karls-Universität Heidelberg
Germany (DE)
Germany (DE)
Regensburg Center for Interventional Immunology
Germany (DE)
Deutsches Krebsforschungszentrum (DKFZ)
Germany (DE)
Ruprecht-Karls-Universität Heidelberg
Germany (DE)
How to cite
APA:
Dettling, S., Stamova, S., Warta, R., Schnoelzer, M., Rapp, C., Rathinasamy, A.,... Herold-Mende, C. (2018). Identification of CRKII, CFL1, CNTN1, NME2, and TKT as novel and frequent T-cell targets in human IDH-mutant glioma. Clinical Cancer Research, 24(12), 2951-2962. https://doi.org/10.1158/1078-0432.CCR-17-1839
MLA:
Dettling, Steffen, et al. "Identification of CRKII, CFL1, CNTN1, NME2, and TKT as novel and frequent T-cell targets in human IDH-mutant glioma." Clinical Cancer Research 24.12 (2018): 2951-2962.
BibTeX: Download