Artikel
Somatic mutations in human leukocyte antigen molecule and antigen presentation pathway genes in malignant glioma
Somatische Mutationen in Genen des Humanen Leukozyten-Antigen-Moleküls und des Antigenpräsentationswegs bei malignen Gliomen
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Autoren
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Sara Schulte
- Heinrich-Heine-Universität Düsseldorf, Genomische Mikrobiologie und Immunität, Institut für medizinische Mikrobiologie und Krankenhaushygiene, Düsseldorf, Deutschland
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Peter Trojok
- Stefan Morsch Stiftung, Birkenfeld, Deutschland
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Moritz Schäfer
- Stefan Morsch Stiftung, Birkenfeld, Deutschland
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Wolfgang Peter
- Stefan Morsch Stiftung, Birkenfeld, Deutschland
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Katrin Lamszus
- Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neurochirurgie, Hamburg, Deutschland
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Manfred Westphal
- Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neurochirurgie, Hamburg, Deutschland
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Alexander Dilthey
- Heinrich-Heine-Universität Düsseldorf, Genomische Mikrobiologie und Immunität, Institut für medizinische Mikrobiologie und Krankenhaushygiene, Düsseldorf, Deutschland
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Malte Mohme
- Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neurochirurgie, Hamburg, Deutschland
| Veröffentlicht: | 25. Mai 2022 |
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Gliederung
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Objective: Immunotherapeutic approaches in cancer are aiming to booster T cell mediated immune responses. Tumor-specific T cell responses recognize tumor cells via human leukocyte antigen (HLA) molecules before a cell specific lysis is engaged. Malignant glioma are known for their immuno evasive and suppressive biology which evades an effective tumor-specific immune response and clinical response to immune checkpoint inhibition. Our aim was to investigate if somatic mutation in the genes of HLA and antigen presentation pathway molecules are present in malignant glioma.
Methods: We performed next generation sequencing of 138 patients, including matched tumor and blood samples from 100 IDHwt glioblastoma, 25 IDHmut astrocytoma and 13 IDHmut oligodendroglioma. Sequencing was performed for HLA class I (HLA-A, -B, -C), HLA class II (HLA-DR, -DP, -DQ), non-classical HLA molecules (HLA-E, -F, -G, -H), MICA/B, TAP1/2 and beta2 microglobulin (B2M). Initially identified calls were validated using targeted nanopore sequencing. All samples were analyzed after written informed consent. The study was approved by the ethics committee (PV4904).
Results: In total, we could identify 74 variants based on Illumina sequencing. Out of these, we found 52 mutations out of which 28 mutations were validated with Oxford nanopore technology and located to the HLA-A (0 mutations) HLA-B (2), HLA-C (1), B2M (2), HLA-DRB1 (0), HLA-DQA1 (4), HLA-DQB1 (4), HLA-DPB1 (1), HLA-E (1), HLA-F (2), HLA-G (3), HLA-H (1), MICA (3), MICB (2), TAP1 (1) and TAP2 (1 mutation) loci. The mutations were found in 30 patients (21.7%). A frequency cutoff of 5% was applied. Some patients harbored up to 7-8 mutations in multiple HLA and antigen presenting pathway genes. Most mutations were found in the MICA (MHC class I polypeptide–related sequence A) gene locus, which is engaged by the NKG2D ligand which is broadly expressed on NK cells, gd and ab T cells.
Conclusion: Our study demonstrates that a diversity of somatic mutations of HLA and antigen presentation pathway genes are found in individual malignant glioma cases. Next we will validate the biological impact on NK and T cell recognition and whether a subclonal enrichment of mutation bearing tumor clones promotes glioma recurrence.
