Müller et al. evaluated two public (NCI and TESLA) and one in-house (Hi-TIDE) datasets and reprocessed WES and RNAseq data, along with immunogenicity assay results for hundreds of mutations and/or neo-peptides. After incorporation of additional complementing features (e.g., proteasomal cleavage, peptide binding stability and oncogene status) a new machine learning (ML) algorithm was trained to prioritize mutations and neo-peptides. The new ML-based approach accurately predicted neoantigen immunogenicity across datasets and increased the number of immunogenic peptides ranked in the top 20 by 30%.
Contributed by Shishir Pant
ABSTRACT: The accurate selection of neoantigens that bind to class I human leukocyte antigen (HLA) and are recognized by autologous T cells is a crucial step in many cancer immunotherapy pipelines. We reprocessed whole-exome sequencing and RNA sequencing (RNA-seq) data from 120 cancer patients from two external large-scale neoantigen immunogenicity screening assays combined with an in-house dataset of 11 patients and identified 46,017 somatic single-nucleotide variant mutations and 1,781,445 neo-peptides, of which 212 mutations and 178 neo-peptides were immunogenic. Beyond features commonly used for neoantigen prioritization, factors such as the location of neo-peptides within protein HLA presentation hotspots, binding promiscuity, and the role of the mutated gene in oncogenicity were predictive for immunogenicity. The classifiers accurately predicted neoantigen immunogenicity across datasets and improved their ranking by up to 30%. Besides insights into machine learning methods for neoantigen ranking, we have provided homogenized datasets valuable for developing and benchmarking companion algorithms for neoantigen-based immunotherapies.
Author Info: (1) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaud
Author Info: (1) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland; Agora Cancer Research Centre, 1011 Lausanne, Switzerland; SIB Swiss Institute of Bioinformatics, Quartier Sorge, Btiment Amphiple, 1015 Lausanne, Switzerland. Electronic address: markus.muller@chuv.ch. (2) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland; Agora Cancer Research Centre, 1011 Lausanne, Switzerland. (3) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland; Agora Cancer Research Centre, 1011 Lausanne, Switzerland. (4) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland; Agora Cancer Research Centre, 1011 Lausanne, Switzerland. (5) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland; Agora Cancer Research Centre, 1011 Lausanne, Switzerland. (6) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland; Agora Cancer Research Centre, 1011 Lausanne, Switzerland. (7) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland; Agora Cancer Research Centre, 1011 Lausanne, Switzerland. (8) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland; Agora Cancer Research Centre, 1011 Lausanne, Switzerland. (9) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland; Agora Cancer Research Centre, 1011 Lausanne, Switzerland. (10) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland; Agora Cancer Research Centre, 1011 Lausanne, Switzerland. (11) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland; Agora Cancer Research Centre, 1011 Lausanne, Switzerland. (12) Agora Cancer Research Centre, 1011 Lausanne, Switzerland; SIB Swiss Institute of Bioinformatics, Quartier Sorge, Btiment Amphiple, 1015 Lausanne, Switzerland. (13) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland; Agora Cancer Research Centre, 1011 Lausanne, Switzerland; Center of Experimental Therapeutics, Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland. (14) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland; Agora Cancer Research Centre, 1011 Lausanne, Switzerland; Center of Experimental Therapeutics, Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland. (15) Ludwig Institute for Cancer Research, University of Lausanne, Agora Center Bugnon 25A, 1005 Lausanne, Switzerland; Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland; Agora Cancer Research Centre, 1011 Lausanne, Switzerland; Center of Experimental Therapeutics, Department of Oncology, Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne, Switzerland. Electronic address: michal.bassani@chuv.ch.
