Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides.

Autor:	Garcia-Marquez MA; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany maria.garcia-marquez@uk-koeln.de.; Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Cologne, Germany., Thelen M; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Cologne, Germany., Bauer E; Institute of Transfusion Medicine, University of Cologne, Cologne, Germany., Maas L; Department of Translational Genomics, University of Cologne, Cologne, Germany., Wennhold K; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Cologne, Germany., Lehmann J; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Cologne, Germany., Keller D; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Cologne, Germany., Nikolić M; Department of Translational Genomics, University of Cologne, Cologne, Germany., George J; Department of Translational Genomics, University of Cologne, Cologne, Germany.; Department of Otorhinolaryngology Head and Neck Surgery, University Hospital Cologne, Cologne, Germany., Zander T; Department I of Internal Medicine and Center for Integrated Oncology (CIO) Aachen Bonn Cologne Duesseldorf, University Hospital Cologne, Cologne, Germany., Schröder W; Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Cologne, Germany., Müller P; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; Institute of Pathology, University of Cologne, Cologne, Germany., Yazbeck AM; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; Institute of Pathology, University of Cologne, Cologne, Germany., Bruns C; Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Cologne, Germany., Thomas R; Department of Translational Genomics, University of Cologne, Cologne, Germany.; Institute of Pathology, University of Cologne, Cologne, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany., Gathof B; Institute of Transfusion Medicine, University of Cologne, Cologne, Germany., Quaas A; Institute of Pathology, University of Cologne, Cologne, Germany., Peifer M; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; Department of Translational Genomics, University of Cologne, Cologne, Germany., Hillmer AM; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; Institute of Pathology, University of Cologne, Cologne, Germany., von Bergwelt-Baildon M; German Cancer Consortium (DKTK), Heidelberg, Germany.; Gene Centre, Ludwig Maximilians University Munich, Munchen, Germany.; Department of Medicine III, Ludwig Maximilians University Munich, Munchen, Germany., Schlößer HA; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Cologne, Germany.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Apr 17; Vol. 12 (4). Date of Electronic Publication: 2024 Apr 17.
DOI:	10.1136/jitc-2023-007268
Abstrakt:	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. Competing Interests: Competing interests: MvB-B: Honoraria for advisory boards, for invited talks from BMS and financial support for research projects from Astellas, Roche and MSD. HAS: Financial support for research projects from Astra Zeneca. All other authors declare no conflicts of interest. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu