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Acta Neuropathol. 2017 Aug;134(2):297-316. doi: 10.1007/s00401-017-1702-1. Epub 2017 Mar 22.

Identification of T cell target antigens in glioblastoma stem-like cells using an integrated proteomics-based approach in patient specimens.

Author information

1
Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
2
Translational Immunology Department, German Cancer Research Center, Heidelberg, Germany.
3
German Cancer Consortium (DKTK), Heidelberg, Germany.
4
Molecular and Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Department of Radiation Oncology, Heidelberg University Medical School, Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCOR), Heidelberg, Germany.
6
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
7
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University, Heidelberg, Germany.
8
Institute of Pathology, Ruprecht-Karls-University, Heidelberg, Germany.
9
NCT Tissue Bank, National Center for Tumor Diseases (NCT), Heidelberg, Germany.
10
Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
11
Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, University of Heidelberg, Heidelberg, Germany.
12
Department of Anaesthesiology, Heidelberg University Hospital, Heidelberg, Germany.
13
Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany. H.Mende@med.uni-heidelberg.de.
14
German Cancer Consortium (DKTK), Heidelberg, Germany. H.Mende@med.uni-heidelberg.de.
15
Sektion Neurochirurgische Forschung, Neurochirurgische Universitätsklinik, INF400, 69120, Heidelberg, Germany. H.Mende@med.uni-heidelberg.de.

Abstract

Glioblastoma (GBM) is a highly aggressive brain tumor and still remains incurable. Among others, an immature subpopulation of self-renewing and therapy-resistant tumor cells-often referred to as glioblastoma stem-like cells (GSCs)-has been shown to contribute to disease recurrence. To target these cells personalized immunotherapy has gained a lot of interest, e.g. by reactivating pre-existing anti-tumor immune responses against GSC antigens. To identify T cell targets commonly presented by GSCs and their differentiated counterpart, we used a proteomics-based separation of GSC proteins in combination with a T cell activation assay. Altogether, 713 proteins were identified by LC-ESI-MS/MS mass spectrometry. After a thorough filtering process, 32 proteins were chosen for further analyses. Immunogenicity of corresponding peptides was tested ex vivo. A considerable number of these antigens induced T cell responses in GBM patients but not in healthy donors. Moreover, most of them were overexpressed in primary GBM and also highly expressed in recurrent GBM tissues. Interestingly, expression of the most frequent T cell target antigens could also be confirmed in quiescent, slow-cycling GSCs isolated in high purity by the DEPArray technology. Finally, for a subset of these T cell target antigens, an association between expression levels and higher T cell infiltration as well as an increased expression of positive immune modulators was observed. In summary, we identified novel immunogenic proteins, which frequently induce tumor-specific T cell responses in GBM patients and were also detected in vitro in therapy-resistant quiescent, slow-cycling GSCs. Stable expression of these T cell targets in primary and recurrent GBM support their suitability for future clinical use.

KEYWORDS:

Heterogeneity; IDH1-wt glioblastoma; Plasticity; Quiescent stem-like cells; T cell target antigen repertoire

PMID:
28332095
DOI:
10.1007/s00401-017-1702-1
[Indexed for MEDLINE]

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