Gene and protein sequence features augment HLA class I ligand predictions

Cell Reports, vol. 43, pp. 114325

Abstract

The sensitivity of malignant tissues to T cell-based immunotherapies depends on the presence of targetable human leukocyte antigen (HLA) class I ligands. Peptide-intrinsic factors, such as HLA class I affinity and proteasomal processing, have been established as determinants of HLA ligand presentation. However, the role of gene and protein sequence features as determinants of epitope presentation has not been systematically evaluated. We perform HLA ligandome mass spectrometry to evaluate the contribution of 7,135 gene and protein sequence features to HLA sampling. This analysis reveals that a number of predicted modifiers of mRNA and protein abundance and turnover, including predicted mRNA methylation and protein ubiquitination sites, inform on the presence of HLA ligands. Importantly, integration of such "hard-coded" sequence features into a machine learning approach augments HLA ligand predictions to a comparable degree as experimental measures of gene expression. Our study highlights the value of gene and protein features for HLA ligand predictions.

Authors 9

1. Kaspar Bresser Aachen Department of Hematology, Leiden University Medical Center

   Leiden University Medical Center · The Netherlands Cancer Institute · Oncode Institute

   Affiliation as printed

   Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, the Netherlands; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands

   Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands

   Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, the Netherlands

2. Benoît P. Nicolet

   Sanquin · Oncode Institute · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Sanquin Blood Supply Foundation, Department of Research, T cell differentiation lab, Amsterdam, The Netherlands; Amsterdam UMC, University of Amsterdam, Landsteiner Laboratory, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands

   Amsterdam UMC, University of Amsterdam, Landsteiner Laboratory, Amsterdam, The Netherlands

   Oncode Institute, Utrecht, The Netherlands

   Sanquin Blood Supply Foundation, Department of Research, T cell differentiation lab, Amsterdam, The Netherlands

3. Anita Jekő

   Utrecht University

   Affiliation as printed

   Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, the Netherlands

4. Wei Wu

   Utrecht University

   Affiliation as printed

   Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, the Netherlands

5. Fabricio Loayza‐Puch

   German Cancer Research Center

   Affiliation as printed

   Translational Control and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany

6. Reuven Agami

   The Netherlands Cancer Institute · Oncode Institute

   Affiliation as printed

   Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands

7. Albert J. R. Heck

   Utrecht University

   Affiliation as printed

   Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, the Netherlands

8. Monika C. Wolkers

   Sanquin · Oncode Institute · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Sanquin Blood Supply Foundation, Department of Research, T cell differentiation lab, Amsterdam, The Netherlands; Amsterdam UMC, University of Amsterdam, Landsteiner Laboratory, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands

   Amsterdam UMC, University of Amsterdam, Landsteiner Laboratory, Amsterdam, The Netherlands

   Oncode Institute, Utrecht, The Netherlands

   Sanquin Blood Supply Foundation, Department of Research, T cell differentiation lab, Amsterdam, The Netherlands

9. Ton N. Schumacher corresponding Aachen Department of Hematology, Leiden University Medical Center

   Leiden University · Leiden University Medical Center · The Netherlands Cancer Institute · Oncode Institute

   Affiliation as printed

   Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, the Netherlands; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: t.schumacher@nki.nl

   Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands

   Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, the Netherlands