Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides
Background The individual HLA-I genotype is associated with cancer, autoimmune diseases and infections. This study elucidates the role of germline homozygosity or allelic imbalance of HLA-I loci in esophago-gastric adenocarcinoma (EGA) and determines the resulting repertoires of potentially immunoge...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2024-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/4/e007268.full |
| _version_ | 1797202346244046848 |
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| author | Alexander Quaas Julie George Philipp Müller Hans Anton Schlößer Michael von Bergwelt-Baildon Martin Thelen Birgit Gathof Martin Peifer Thomas Zander Axel M Hillmer Christiane Bruns Diandra Keller Jonas Lehmann Kerstin Wennhold Eugen Bauer Maria Alejandra Garcia-Marquez Roman Thomas Lukas Maas Miloš Nikolić Wolfgang Schröder Ali M Yazbeck |
| author_facet | Alexander Quaas Julie George Philipp Müller Hans Anton Schlößer Michael von Bergwelt-Baildon Martin Thelen Birgit Gathof Martin Peifer Thomas Zander Axel M Hillmer Christiane Bruns Diandra Keller Jonas Lehmann Kerstin Wennhold Eugen Bauer Maria Alejandra Garcia-Marquez Roman Thomas Lukas Maas Miloš Nikolić Wolfgang Schröder Ali M Yazbeck |
| author_sort | Alexander Quaas |
| collection | DOAJ |
| description | Background The individual HLA-I genotype is associated with cancer, autoimmune diseases and infections. This study elucidates the role of germline homozygosity or allelic imbalance of HLA-I loci in esophago-gastric adenocarcinoma (EGA) and determines the resulting repertoires of potentially immunogenic peptides.Methods HLA genotypes and sequences of either (1) 10 relevant tumor-associated antigens (TAAs) or (2) patient-specific mutation-associated neoantigens (MANAs) were used to predict good-affinity binders using an in silico approach for MHC-binding (www.iedb.org). Imbalanced or lost expression of HLA-I-A/B/C alleles was analyzed by transcriptome sequencing. FluoroSpot assays and TCR sequencing were used to determine peptide-specific T-cell responses.Results We show that germline homozygosity of HLA-I genes is significantly enriched in EGA patients (n=80) compared with an HLA-matched reference cohort (n=7605). Whereas the overall mutational burden is similar, the repertoire of potentially immunogenic peptides derived from TAAs and MANAs was lower in homozygous patients. Promiscuity of peptides binding to different HLA-I molecules was low for most TAAs and MANAs and in silico modeling of the homozygous to a heterozygous HLA genotype revealed normalized peptide repertoires. Transcriptome sequencing showed imbalanced expression of HLA-I alleles in 75% of heterozygous patients. Out of these, 33% showed complete loss of heterozygosity, whereas 66% had altered expression of only one or two HLA-I molecules. In a FluoroSpot assay, we determined that peptide-specific T-cell responses against NY-ESO-1 are derived from multiple peptides, which often exclusively bind only one HLA-I allele.Conclusion The high frequency of germline homozygosity in EGA patients suggests reduced cancer immunosurveillance leading to an increased cancer risk. Therapeutic targeting of allelic imbalance of HLA-I molecules should be considered in EGA. |
| first_indexed | 2024-04-24T08:01:58Z |
| format | Article |
| id | doaj.art-afc5d656bb5b494e9b31c5d4b6a0c547 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-24T08:01:58Z |
| publishDate | 2024-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-afc5d656bb5b494e9b31c5d4b6a0c5472024-04-17T16:55:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-04-0112410.1136/jitc-2023-007268Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptidesAlexander Quaas0Julie George1Philipp Müller2Hans Anton Schlößer3Michael von Bergwelt-Baildon4Martin Thelen5Birgit Gathof6Martin Peifer7Thomas Zander8Axel M Hillmer9Christiane Bruns10Diandra Keller11Jonas Lehmann12Kerstin Wennhold13Eugen Bauer14Maria Alejandra Garcia-Marquez15Roman Thomas16Lukas Maas17Miloš Nikolić18Wolfgang Schröder19Ali M Yazbeck206Institute of Pathology, University Hospital Cologne, Cologne, Germany2 Institute of Health Informatics, University College London, London, UK1 Center for Molecular Medicine Cologne, University of Cologne, Cologne, GermanyCenter for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, GermanyDepartment of Hematology and Oncology, University Hospital Munich Campus Grosshadern, Munich, GermanyCenter for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, GermanyInstitute of Transfusion Medicine, University of Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany3Department of Translational Genomics, Centre for Molecular Medicine Cologne, Cologne, Germany6 Department I of Internal Medicine and Center for Integrated Oncology (CIO) Aachen Bonn Cologne Duesseldorf, University Hospital Cologne, Cologne, Germany12 Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University Hospital Cologne, Cologne, GermanyDepartment of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, GermanyCenter for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, GermanyCenter for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, GermanyCenter for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, GermanyInstitute of Transfusion Medicine, University of Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, GermanyCenter for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany1University of Cologne, Cologne, Germany4 Department of Translational Genomics, University of Cologne, Cologne, Germany4 Department of Translational Genomics, University of Cologne, Cologne, Germany2 Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Cologne, Germany1 Center for Molecular Medicine Cologne, University of Cologne, Cologne, GermanyBackground The individual HLA-I genotype is associated with cancer, autoimmune diseases and infections. This study elucidates the role of germline homozygosity or allelic imbalance of HLA-I loci in esophago-gastric adenocarcinoma (EGA) and determines the resulting repertoires of potentially immunogenic peptides.Methods HLA genotypes and sequences of either (1) 10 relevant tumor-associated antigens (TAAs) or (2) patient-specific mutation-associated neoantigens (MANAs) were used to predict good-affinity binders using an in silico approach for MHC-binding (www.iedb.org). Imbalanced or lost expression of HLA-I-A/B/C alleles was analyzed by transcriptome sequencing. FluoroSpot assays and TCR sequencing were used to determine peptide-specific T-cell responses.Results We show that germline homozygosity of HLA-I genes is significantly enriched in EGA patients (n=80) compared with an HLA-matched reference cohort (n=7605). Whereas the overall mutational burden is similar, the repertoire of potentially immunogenic peptides derived from TAAs and MANAs was lower in homozygous patients. Promiscuity of peptides binding to different HLA-I molecules was low for most TAAs and MANAs and in silico modeling of the homozygous to a heterozygous HLA genotype revealed normalized peptide repertoires. Transcriptome sequencing showed imbalanced expression of HLA-I alleles in 75% of heterozygous patients. Out of these, 33% showed complete loss of heterozygosity, whereas 66% had altered expression of only one or two HLA-I molecules. In a FluoroSpot assay, we determined that peptide-specific T-cell responses against NY-ESO-1 are derived from multiple peptides, which often exclusively bind only one HLA-I allele.Conclusion The high frequency of germline homozygosity in EGA patients suggests reduced cancer immunosurveillance leading to an increased cancer risk. Therapeutic targeting of allelic imbalance of HLA-I molecules should be considered in EGA.https://jitc.bmj.com/content/12/4/e007268.full |
| spellingShingle | Alexander Quaas Julie George Philipp Müller Hans Anton Schlößer Michael von Bergwelt-Baildon Martin Thelen Birgit Gathof Martin Peifer Thomas Zander Axel M Hillmer Christiane Bruns Diandra Keller Jonas Lehmann Kerstin Wennhold Eugen Bauer Maria Alejandra Garcia-Marquez Roman Thomas Lukas Maas Miloš Nikolić Wolfgang Schröder Ali M Yazbeck Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides Journal for ImmunoTherapy of Cancer |
| title | Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides |
| title_full | Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides |
| title_fullStr | Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides |
| title_full_unstemmed | Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides |
| title_short | Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides |
| title_sort | germline homozygosity and allelic imbalance of hla i are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides |
| url | https://jitc.bmj.com/content/12/4/e007268.full |
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