Article (Scientific journals)
Tumor antigens preferentially derive from unmutated genomic sequences in melanoma and non-small cell lung cancer.
Apavaloaei, Anca; Zhao, Qingchuan; Hesnard, Leslie et al.
2025In Nature Cancer
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Keywords :
Oncology; Cancer Research
Abstract :
[en] Melanoma and non-small cell lung cancer (NSCLC) display exceptionally high mutational burdens. Hence, immune targeting in these cancers has primarily focused on tumor antigens (TAs) predicted to derive from nonsynonymous mutations. Using comprehensive proteogenomic analyses, we identified 589 TAs in cutaneous melanoma (n = 505) and NSCLC (n = 90). Of these, only 1% were derived from mutated sequences, which was explained by a low RNA expression of most nonsynonymous mutations and their localization outside genomic regions proficient for major histocompatibility complex (MHC) class I-associated peptide generation. By contrast, 99% of TAs originated from unmutated genomic sequences specific to cancer (aberrantly expressed tumor-specific antigens (aeTSAs), n = 220), overexpressed in cancer (tumor-associated antigens (TAAs), n = 165) or specific to the cell lineage of origin (lineage-specific antigens (LSAs), n = 198). Expression of aeTSAs was epigenetically regulated, and most were encoded by noncanonical genomic sequences. aeTSAs were shared among tumor samples, were immunogenic and could contribute to the response to immune checkpoint blockade observed in previous studies, supporting their immune targeting across cancers.
Disciplines :
Oncology
Author, co-author :
Apavaloaei, Anca ;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada ; Department of Medicine, University of Montreal, Montreal, Quebec, Canada
Zhao, Qingchuan;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada ; Department of Medicine, University of Montreal, Montreal, Quebec, Canada
Hesnard, Leslie ;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada
Cahuzac, Maxime ;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada
Durette, Chantal;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada
Larouche, Jean-David;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada ; Department of Medicine, University of Montreal, Montreal, Quebec, Canada
Hardy, Marie-Pierre;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada
Vincent, Krystel;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada
Brochu, Sylvie;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada
Laverdure, Jean-Philippe ;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada
Lanoix, Joël;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada
Courcelles, Mathieu ;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada
Gendron, Patrick;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada
Lajoie, Mathieu ;  Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
Ruiz Cuevas, Maria Virginia ;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada ; Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, Quebec, Canada
Kina, Eralda;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada ; Department of Medicine, University of Montreal, Montreal, Quebec, Canada
Perrault, Julie;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada
Humeau, Juliette;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada ; Department of Medicine, University of Montreal, Montreal, Quebec, Canada
Ehx, Grégory  ;  Université de Liège - ULiège > Département des sciences cliniques ; Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada ; Walloon Excellence in Life Sciences and Biotechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium
Lemieux, Sébastien ;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada ; Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, Quebec, Canada
Watson, Ian R ;  Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada ; Department of Biochemistry, McGill University, Montreal, Quebec, Canada
Speiser, Daniel E ;  Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Bassani-Sternberg, Michal ;  Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland ; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
Thibault, Pierre ;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. pierre.thibault@umontreal.ca ; Department of Chemistry, University of Montreal, Montreal, Quebec, Canada. pierre.thibault@umontreal.ca
Perreault, Claude ;  Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. claude.perreault@umontreal.ca ; Department of Medicine, University of Montreal, Montreal, Quebec, Canada. claude.perreault@umontreal.ca
More authors (15 more) Less
Language :
English
Title :
Tumor antigens preferentially derive from unmutated genomic sequences in melanoma and non-small cell lung cancer.
Publication date :
22 May 2025
Journal title :
Nature Cancer
eISSN :
2662-1347
Publisher :
Nature, England
Peer reviewed :
Peer Reviewed verified by ORBi
Funding text :
We thank E. Audemard from the IRIC Bioinformatics Platform for discussions and suggestions for exploratory analyses. We are indebted to B. Fairfax and R. Watson (University of Oxford) for valuable discussions and exploratory analyses of TCR-seq data and to C. Robert, D. Gautheret and H. Herrmann (Gustave Roussy Institute) for insightful discussions on ICB resistance in melanoma. We also thank the IRIC genomics core facility staff for technical assistance with RNA-seq. In addition, we are grateful to Genentech for access to data from Banchereau et al. and to the GTEx Consortium, TCGA, the Melanoma Genome Sequencing Project and the authors of previous studies who granted us 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 SynergiQc program (to C.P. and P.T.) and the Fonds Vaccins Th\u00E9rapeutiques Contre le Cancer (to C.P.). A.A. was supported by a doctoral studentship from the Fonds de Recherche du Qu\u00E9bec\u2014Sant\u00E9. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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