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Identifizierung von Tumor-assoziierten Antigenen in IDH-mutierten Gliomen

Dettling, Steffen

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Abstract

Gliomas are tumors of the central nervous system which are classified by the World Health Organization (WHO) from grade I to grade IV, according to the degree of malignancy as defined by histopathological and molecular criteria. Mutations in the isocitrate dehydrogenase (IDHmut) genes are a common cha- racteristic for lower grade gliomas (LGGs, WHO◦II/◦III) and have been shown to be a prognostic marker for a favorable clinical outcome. The metabolic and biologic consequences by IDHmut-induced epigentic alterations have changed our perceptions of gliomas and demonstrated the demand to consider IDHmut LGGs separately. Despite a favourable prognosis, IDHmut LGGs remain deadly since there is still a lack of effective therapies. For that reason, immunotherapeutic approaches are gaining increasing attention. Due to the limited number of known T cell targets in IDHmut gliomas, we aimed to elucidate the reper- toire of spontaneous T cell responses in IDHmut LGGs by performing an unbiased proteomic approach. We systematically analyzed the proteome of IDHmut LGG samples (n = 4) by fractionating tumor tissue lysates and testing resulting fractions by IFN-γ enzyme linked immunospot (ELISpot) assay for recogni- tion by the patients T cell repertoire. Immunogenic tumor protein fractions were subsequently analyzed by quantitative mass spectrometry resulting in 2897 identified proteins. Based on a thorough filter pro- cess 79 proteins have been selected as potential target antigens and were validated in IFN-γ ELISpots by means of synthetic in silico predicted 50-mer peptides. 26 of these were recognized by autologous T cells and were tested in further IDHmut LGG patients as well as in healthy donors. Tumor-specific T cell responses in up to 50 % of IDHmut LGG patients were observed for CRKII, CFL1, CNTN1, NME2, and TKT. Beside the immunogenicity of the antigens, we further characterized their role in oncogenesis, the antigen-specificity as well as the expression levels in the tumor and on glioma stem-like cells (GSCs). By using immunohistochemistry and gene expression analysis we found that four out of five of the most immunogenic tumor-associated antigens (CRKII, CFL1, CNTN1 and NME2) were expressed in astro- cytic and oligodendroglial tumors as well as in IDHmut GSCs, while being almost absent in normal brain tissues. Finally, we identified HLA-A*02-restricted reactive epitopes for CRKII (ALALEVGEL), NME2 (MVWEGLNVV), and TKT (FLAEAELLNL) which are recognized by up to 1.5 % of antigen-specific pe- ripheral cytotoxic T cells in IDHmut LGG patients. By analyzing the repertoire of T cell target antigens in IDHmut LGG patients, we identified four novel immunogenic antigens and even confirmed their expression on IDHmut GSCs, highlighting their potential as T cell targets for the development of new immunotherapeutic approaches.

Item Type: Dissertation
Supervisor: Herold-Mende, Prof. Dr. Christel
Date of thesis defense: 19 September 2017
Date Deposited: 06 Oct 2017 09:36
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
Controlled Keywords: Tumor-assoziierte Antigene, IDH mutierte Gliome, Tumorimmunologie
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