Deciphering HLA motifs across HLA peptidomes correctly predicts neo-antigens and identifies allostery in HLA specificity

Bassani-Sternberg, M.; Chong, C.; Guillaume, P.; Solleder, M.; Pak, H.; Gannon, P. O.; Kandalaft, L. E.; Coukos, G.; Gfeller, D.

doi:10.1101/098780

bioRxiv · 10.1101/098780

Deciphering HLA motifs across HLA peptidomes correctly predicts neo-antigens and identifies allostery in HLA specificity

Bassani-Sternberg, M.·Chong, C.·Guillaume, P.·Solleder, M.·Pak, H.·Gannon, P. O.·Kandalaft, L. E.·Coukos, G.·Gfeller, D.

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Abstract

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 allosteric modulation of the binding specificity of HLA-I alleles and we unravel the underlying mechanisms by protein structure analysis, mutagenesis and in vitro binding assays.

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Bassani-Sternberg, M., Chong, C., Guillaume, P., Solleder, M., Pak, H., Gannon, P. O., Kandalaft, L. E., Coukos, G., Gfeller, D.. 2017-01-06. Deciphering HLA motifs across HLA peptidomes correctly predicts neo-antigens and identifies allostery in HLA specificity. https://doi.org/10.1101/098780

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