Analyse der Immunpeptidome von Ependymomen und Oropharyngealen Plattenepithelkarzinomen mittels Massenspektrometrie

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Dokumentart: PhDThesis
Date: 2022-11-02
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biochemie
Advisor: Stevanović, Stefan (Prof. Dr.)
Day of Oral Examination: 2020-11-02
DDC Classifikation: 500 - Natural sciences and mathematics
570 - Life sciences; biology
Keywords: Immunologie , Massenspektrometrie , Ependymom , HLA , Onkologie , Immuntherapie
Other Keywords: Immunpeptidomik
Oropharyngeales Plattenepithelkarzinom
mass spectrometry
oropharyngeal squamous cell carcinoma
cancer immunotherapy
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Presentation of antigens by human leukocyte antigen (HLA) molecules on cell surfaces and their recognition through T cells is essential for the initiation of an adaptive immune response. The analysis of the entirety of HLA-presented antigens, referred to as immunopeptidome or HLA ligandome, plays an important role for the development of immunotherapeutic methods to treat cancer patients. The present work addresses the immunopeptidomic analyses in two different tumor entities. Ependymomas are a heterogenous tumor entity of the central nervous system and a long-term disease control is often challenging. Oropharyngeal squamous cell carcinomas (OPSCCs) belong to the head and neck tumors. Besides smoking and alcohol consumption, infections with oncogenic human papilloma viruses (HPV) are an important risk factor for the development of OPSCCs. Due to a rising number of HPV infections, the incidence rate of OPSCCs is increasing. HLA ligands were isolated from tumor tissue samples by immunoaffinity chromatography and were subsequently analyzed through liquid chromatography followed by tandem mass spectrometry (MS/MS). This method was applied to 22 ependymomas and 40 OPSCCs. In addition, the immunopeptidomic data of five tonsil tissue samples were collected and served as benign reference for the OPSCC cohort. The MS-based analysis enabled the detection of 6,801 HLA class I and 3,855 HLA class II ligands in the ependymomas as well as of 25,228 HLA class I and 15,203 HLA class II-ligands in the OPSCCs. By detailed investigation of the immunopeptidomic datasets, potential tumor-associated antigens (TAAs) presented by different HLA allotypes were identified. This included 8 ependymoma TAAs of which the most frequent peptides derived from the source proteins CCDC180 and DNAH6. 15 OPSCC TAAs were identified, of which the most frequent peptides derived from the source proteins UBD and PKP1. Additionally, HPV-associated differences between the HLA ligandomes as well as between the RNA transcriptomes of HPV⁺ and HPV⁻ OPSCCs were revealed. These differences partly concerned the selected TAAs indicating a benefit for the consideration of the HPV status during immunotherapeutic target selection. The suitability of the selected TAAs as immunotherapeutic targets must be further evaluated in future studies. Still, the results illustrate that both tumor entities provide opportunities for immunotherapeutic approaches such as personalized or semi-personalized peptide vaccinations. Hence, by mapping the immunopeptidomes, a major step towards the development of immunotherapeutic strategies for the treatment of ependymoma and OPSCC patients was taken.

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