Journal Article

Deciphering HLA-I motifs across HLA peptidomes improves neo-antigen predictions and identifies allostery regulating HLA specificity

Bassani-Sternberg, Michal, Guillaume, Philippe, Kandalaft, Lana E., Chong, Chloé, Coukos, George, Gfeller, David, Gannon, Philippe O., Solleder, Marthe, Pak, HuiSong

2017

Overview

The precise identification of Human Leukocyte Antigen class I (HLA-I) binding motifs plays a central role in our ability to understand and predict (neo-)antigen presentation in infectious diseases and cancer. Here, by exploiting co-occurrence of HLA-I alleles across ten newly generated as well as forty public HLA peptidomics datasets comprising more than 115,000 unique peptides, we show that we can rapidly and accurately identify many HLA-I binding motifs and map them to their corresponding alleles without any a priori knowledge of HLA-I binding specificity. Our approach recapitulates and refines known motifs for 43 of the most frequent alleles, uncovers new motifs for 9 alleles that up to now had less than five known ligands and provides a scalable framework to incorporate additional HLA peptidomics studies in the future. The refined motifs improve neo-antigen and cancer testis antigen predictions, indicating that unbiased HLA peptidomics data are ideal for in silico predictions of neo-antigens from tumor exome sequencing data. The new motifs further reveal distant modulation of the binding specificity at P2 for some HLA-I alleles by residues in the HLA-I binding site but outside of the B-pocket and we unravel the underlying mechanisms by protein structure analysis, mutagenesis and in vitro binding assays.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alleles / Amino Acid Motifs - genetics / Antigen (tumor-associated) / Antigen presentation / Antigens / Authorship / Binding sites / Binding Sites - genetics / Bioinformatics / Biology and Life Sciences / Cancer / Datasets / Funding / Genomes / Health aspects / Histocompatibility antigen HLA / Histocompatibility antigens / Histocompatibility Antigens Class I - chemistry / Histocompatibility Antigens Class I - genetics / Histocompatibility Antigens Class I - metabolism / HLA antigens / HLA histocompatibility antigens / Humans / Immunotherapy / In vitro methods and tests / Infectious diseases / Ligands / Lymphocytes / Medical research / Medicine and Health Sciences / Melanoma / Mutagenesis / Oncology / Peptides / Peptides - analysis / Peptides - chemistry / Peptides - genetics / Peptides - metabolism / Physical Sciences / Protein Binding - genetics / Protein structure / Proteins / Proteome - chemistry / Proteome - genetics / Proteome - metabolism / Proteomics - methods / Research and Analysis Methods / Structural analysis