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Immunotherapy

Proteogenomic-based discovery of minor histocompatibility antigens with suitable features for immunotherapy of hematologic cancers

Leukemia volume 30, pages 1344–1354 (2016)Cite this article

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Abstract

Pre-clinical studies have shown that injection of allogeneic T cells primed against a single minor histocompatibility antigen (MiHA) could cure hematologic cancers (HC) without causing any toxicity to the host. 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, out of >6000 MiHAs, we have identified a set of 39 MiHAs that share optimal features for immunotherapy of HCs. These ‘optimal MiHAs’ are coded by common alleles of genes that are preferentially expressed in hematopoietic cells. Bioinformatic modeling based on MiHA allelic frequencies showed that the 39 optimal MiHAs 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.

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Acknowledgements

We are most grateful to our blood donors. We thank all members of the PCITP (Personalized Cancer Immunotherapy Program), including Manon Richaud, Marc Lussier, Jean-Guy Némorin and members of the PCITP research oversight committee, for thoughtful advice and suggestions. We also thank Manuel Buscarlet and Alexandre Rouette for help with exome sequencing and analysis of TCGA data, respectively. This work was supported by grants from the Canadian Cancer Society Research Institute (grant no. 701564) and the PCITP, which is funded by Genome Canada, Genome Quebec, the Canadian Institutes of Health Research and AmorChem. CP and PT hold Canada Research Chairs in Immunobiology, and Proteomics and Bioanalytical Spectrometry, respectively. The Institute for Research in Immunology and Cancer and Hôpital Maisonneuve-Rosemont Research Center are supported in part by the Canada Foundation for Innovation and the Fonds de Recherche Santé Québec.

Author contributions

DPG designed the study, performed experiments, analyzed data and wrote first draft of the manuscript. AR, CD and EB performed MS experiments, analyses and validation. JPL and OC-L developed bioinformatics tools and carried out predictions. CCo and HP performed experiments. CCa, VJ, DCR and JSD designed, performed and analyzed immunogenicity experiments. SL designed the study and reviewed bioinformatic analyses. PT and CP conceived the study, reviewed experiments, analyzed data, wrote the manuscript and contributed equally as senior authors. All authors edited and approved the final version of the manuscript.

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Authors and Affiliations

  1. Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada,

    D P Granados, A Rodenbrock, J-P Laverdure, C Côté, O Caron-Lizotte, H Pearson, C Durette, E Bonneil, S Lemieux, P Thibault & C Perreault

  2. Department of Medicine, Université de Montréal, Montréal, QC, Canada,

    D P Granados, H Pearson, D C Roy, J-S Delisle & C Perreault

  3. Department of Informatics and Operational Research, Université de Montréal, Montréal, QC, Canada

    J-P Laverdure & S Lemieux

  4. Centre de recherche de l’Hôpital Maisonneuve-Rosemont, Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada,

    C Carli, V Janelle, D C Roy & J-S Delisle

  5. Division of Hematology-Oncology, Hôpital Maisonneuve-Rosemont, Montreal, QC, Canada

    D C Roy, J-S Delisle & C Perreault

  6. Department of Chemistry, Université de Montréal, Montréal, QC, Canada,

    P Thibault

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  1. D P Granados
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Correspondence to P Thibault or C Perreault.

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Competing interests

CP, PT, SL, DPG and JSD are inventors on a patent application filed by Université de Montréal that covers MiHAs reported in this manuscript. The remaining authors declare no conflict of interest.

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Granados, D., Rodenbrock, A., Laverdure, JP. et al. Proteogenomic-based discovery of minor histocompatibility antigens with suitable features for immunotherapy of hematologic cancers. Leukemia 30, 1344–1354 (2016). https://doi.org/10.1038/leu.2016.22

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