APA
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Garcia-Marquez, M., Thelen, M., Bauer, E., Maas, L., Wennhold, K., Lehmann, J., … Schlößer, H. (2024). 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.
Chicago/Turabian
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Garcia-Marquez, M., M. Thelen, Eugen Bauer, L. Maas, K. Wennhold, J. Lehmann, Diandra Keller, et al. “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 (2024).
MLA
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Garcia-Marquez, M., et al. “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, 2024.
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@article{m2024a,
title = {Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides},
year = {2024},
journal = {Journal for ImmunoTherapy of Cancer},
author = {Garcia-Marquez, M. and Thelen, M. and Bauer, Eugen and Maas, L. and Wennhold, K. and Lehmann, J. and Keller, Diandra and Nikolić, Miloš and George, Julie and Zander, Thomas and Schröder, W. and Müller, P. and Yazbeck, Ali M and Bruns, Christiane J. and Thomas, Roman and Gathof, Birgit and Quaas, A. and Peifer, M. and Hillmer, Axel M. and von Bergwelt-Baildon, M. and Schlößer, H.}
}
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.