CP: stem cell research; cancer immunotherapy; induced pluripotent stem cells; major histocompatibility complex class I; mass spectrometry; tumor-specific antigens; Histocompatibility Antigens Class I; Peptides; Animals; Histocompatibility Antigens Class I/metabolism; Humans; Mice; Peptides/metabolism; Induced Pluripotent Stem Cells; Neoplasms/metabolism; Pluripotent Stem Cells/metabolism; Neoplasms; Pluripotent Stem Cells; Biochemistry, Genetics and Molecular Biology (all); General Biochemistry, Genetics and Molecular Biology
Résumé :
[en] Previous reports showed that mouse vaccination with pluripotent stem cells (PSCs) induces durable anti-tumor immune responses via T cell recognition of some elusive oncofetal epitopes. We characterize the MHC I-associated peptide (MAP) repertoire of human induced PSCs (iPSCs) using proteogenomics. Our analyses reveal a set of 46 pluripotency-associated MAPs (paMAPs) absent from the transcriptome of normal tissues and adult stem cells but expressed in PSCs and multiple adult cancers. These paMAPs derive from coding and allegedly non-coding (48%) transcripts involved in pluripotency maintenance, and their expression in The Cancer Genome Atlas samples correlates with source gene hypomethylation and genomic aberrations common across cancer types. We find that several of these paMAPs were immunogenic. However, paMAP expression in tumors coincides with activation of pathways instrumental in immune evasion (WNT, TGF-β, and CDK4/6). We propose that currently available inhibitors of these pathways could synergize with immune targeting of paMAPs for the treatment of poorly differentiated cancers.
Disciplines :
Biochimie, biophysique & biologie moléculaire
Auteur, co-auteur :
Apavaloaei, Anca; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada, Department of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
Hesnard, Leslie; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Hardy, Marie-Pierre; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Benabdallah, Basma; CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada
Ehx, Grégory ; Université de Liège - ULiège > Département des sciences cliniques ; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Thériault, Catherine; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Laverdure, Jean-Philippe; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Durette, Chantal; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Lanoix, Joël; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Courcelles, Mathieu; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Noronha, Nandita; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada, Department of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
Chauhan, Kapil Dev; Faculty of Health Sciences, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada
Lemieux, Sébastien; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada, Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
Beauséjour, Christian; CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada, Department of Pharmacology and Physiology, University of Montreal, Montreal, QC H3T 1J4, Canada
Bhatia, Mick; Faculty of Health Sciences, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
Thibault, Pierre; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada, Department of Chemistry, University of Montreal, Montreal, QC H3T 1J4, Canada. Electronic address: pierre.thibault@umontreal.ca
Perreault, Claude ; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada, Department of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada. Electronic address: claude.perreault@umontreal.ca
We wish to thank Qingchuan Zhao, Jean-David Larouche, Assya Trofimov, Maria Virginia Ruiz Cuevas, Eralda Kina, and Krystel Vincent for valuable discussions and suggestions and help with preliminary exploratory analyses. We are grateful to Raphaëlle Lambert, Jennifer Huber, Sarah Boissel, and the IRIC genomics core facility staff for technical assistance with RNA-seq and Patrick Gendron from the IRIC bioinformatics platform for help with RNA-seq and TCGA data analyses. We also thank Dr. Hannah Carter (UC San Diego) for providing the HLA typing information for TCGA patients and the NIH Tetramer Core Facility for providing the tetramers used in this study. Finally, we thank the TCGA and the GTEx Consortium for access to data that enabled this study. This study was supported by grants from the Canadian Cancer Society ( 705604 ) (to C.P. and P.T.), the Canadian Institutes of Health Research ( FDN 148400 ) (to C.P.), The Oncopole (EMC 2 Grant) (to C.P. and P.T.), and the Fonds Vaccins Thérapeutiques Contre le Cancer (to C.P.). A.A. is supported by doctoral studentships from the IRIC , The Cole Foundation , and the Fonds de Recherche du Québec - Santé . For the Bhatia program, this work was supported by the Canada Chair Program (Tier 1) for Human Stem Cell Biology and DeGroote Chair in Stem Cell Biology to M.B. and Canadian Institutes of Health Research (CIHR) foundation grant FRN 159925 to M.B. approved by the Stem Cell Oversight Committee in Canada.We wish to thank Qingchuan Zhao, Jean-David Larouche, Assya Trofimov, Maria Virginia Ruiz Cuevas, Eralda Kina, and Krystel Vincent for valuable discussions and suggestions and help with preliminary exploratory analyses. We are grateful to Raphaëlle Lambert, Jennifer Huber, Sarah Boissel, and the IRIC genomics core facility staff for technical assistance with RNA-seq and Patrick Gendron from the IRIC bioinformatics platform for help with RNA-seq and TCGA data analyses. We also thank Dr. Hannah Carter (UC San Diego) for providing the HLA typing information for TCGA patients and the NIH Tetramer Core Facility for providing the tetramers used in this study. Finally, we thank the TCGA and the GTEx Consortium for access to data that enabled this study. This study was supported by grants from the Canadian Cancer Society (705604) (to C.P. and P.T.), the Canadian Institutes of Health Research (FDN 148400) (to C.P.), The Oncopole (EMC2 Grant) (to C.P. and P.T.), and the Fonds Vaccins Thérapeutiques Contre le Cancer (to C.P.). A.A. is supported by doctoral studentships from the IRIC, The Cole Foundation, and the Fonds de Recherche du Québec - Santé. For the Bhatia program, this work was supported by the Canada Chair Program (Tier 1) for Human Stem Cell Biology and DeGroote Chair in Stem Cell Biology to M.B. and Canadian Institutes of Health Research (CIHR) foundation grant FRN 159925 to M.B. approved by the Stem Cell Oversight Committee in Canada. A.A. M.-P.H. and C.P. designed the study. A.A. performed the cell culture experiments, cytotoxicity assays, main bioinformatic analyses, and data interpretation and wrote the first manuscript draft. C.D. and J.L. performed mass spectrometry experiments. L.H. and C.T. performed in vitro immunogenicity assays. B.B. performed trilineage differentiation assays. M.-P.H. and D.K.C. assisted with preliminary iPSC experiments. N.N. provided assistance with AML cell culture. M.-P.H. G.E. J.-P.L. and M.C. contributed to bioinformatic analyses. M.-P.H. L.H. G.E. B.B. N.N. S.L. C.B. M.B. P.T. and C.P. contributed to the analysis and interpretation of data. All authors edited and approved the final manuscript. A.A. M.-P.H. P.T. and C.P. are named inventors on a patent application filed by Université de Montréal and covering antigens described in this article.
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