Reference
Reference TypeDual
TitleProteogenomics uncovers a vast repertoire of human minor histocompatibility antigens presented by common HLA allotypes
Submission TitleMHC class I-associated peptides derive from selective regions of the human genome.
AuthorsDiana P. Granados, Anja Rodenbrock, Jean-Philippe Laverdure, Caroline Côté, Olivier Caron-Lizotte, Hillary Pearson, Cédric Carli, Valérie Janelle, Chantal Durette, Eric Bonneil, Denis-Claude Roy, Jean-Sébastien Delisle , Sébastien Lemieux, Pierre Thibault, Claude Perreault
Submission AuthorsHillary Pearson; Tariq Daouda; Diana Paola Granados; Chantal Durette; Eric Bonneil; Mathieu Courcelles; Anja Rodenbrock; Jean-Philippe Laverdure; Caroline Côté; Sylvie Mader; Sébastien Lemieux; Pierre Thibault; Claude Perreault
AffiliationsUniversité de Montréal, Montréal
Submission Affiliations.
JournalJ Clin Invest
SubmitterDiana P. Granados
Year2015
Submission Date2016
AbstractAllogeneic hematopoietic cell transplantation (AHCT) has cured hundreds of thousands of patients with hematologic cancers (HCs) via the graft-vs.-leukemia (GVL) effect mediated by T cells specific for minor histocompatibility antigens (MiHAs). MiHAs are peptides coded by polymorphic genomic regions and presented at the cell surface by MHC molecules. Nevertheless, conventional AHCT remains a rudimentary and toxic form of immunotherapy because unselected allogeneic T cells react against a multitude of host MiHAs (found in all tissues) and thereby induce graft-vs.-host disease (GVHD) in most recipients. Pre-clinical studies have shown that injection of T cells primed against a single MiHA could cure leukemia without causing any GVHD. However, translation of this approach in humans has been hampered by the paucity of molecularly defined human MiHAs. Using a novel proteogenomic approach, we have analyzed cells from 13 volunteers and discovered a vast repertoire of MiHAs presented by the most common HLA haplotype in European Americans: HLA-A*02:01;B*44:03. Notably, we have identified a set of 39 MiHAs that share optimal features for immunotherapy of HCs and would enable MiHA-targeted immunotherapy of practically all HLA-A*02:01;B*44:03 patients. Further extension of this strategy to a few additional HLA haplotypes would allow treatment of almost all patients.
Submission AbstractMHC class I-associated peptides (MAPs) define the immune self for CD8+ T lymphocytes and are key targets of cancer immunosurveillance. Here, the goals of our work were to determine whether the entire set of protein-coding genes could generate MAPs and whether specific features influence the ability of discrete genes to generate MAPs. Using proteogenomics, we have identified 25,270 MAPs isolated from the B lymphocytes of 18 individuals who collectively expressed 27 high-frequency HLA-A,B allotypes. The entire MAP repertoire presented by these 27 allotypes covered only 10% of the exomic sequences expressed in B lymphocytes. Indeed, 41% of expressed protein-coding genes generated no MAPs, while 59% of genes generated up to 64 MAPs, often derived from adjacent regions and presented by different allotypes. We next identified several features of transcripts and proteins associated with efficient MAP production. From these data, we built a logistic regression model that predicts with good accuracy whether a gene generates MAPs. Our results show preferential selection of MAPs from a limited repertoire of proteins with distinctive features. The notion that the MHC class I immunopeptidome presents only a small fraction of the protein-coding genome for monitoring by the immune system has profound implications in autoimmunity and cancer immunology.
Curation Last Updated2025-02-10 19:03:56
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