Tumor antigens preferentially derive from unmutated genomic sequences in melanoma and non-small cell lung cancer
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.
Authors
- Leslie Hesnard (ORCID: https://orcid.org/0000-0002-4623-7703)
- Sylvie Brochu (ORCID: https://orcid.org/0000-0002-4665-0936)
- Chantal Durette (ORCID: https://orcid.org/0000-0002-6692-1262)
- Pierre Thibault (ORCID: https://orcid.org/0000-0001-5993-0331)
- Joël Lanoix (ORCID: https://orcid.org/0000-0001-7073-9298)
- Juliette Humeau (ORCID: https://orcid.org/0000-0002-1991-8001)
- Marie‐Pierre Hardy (ORCID: https://orcid.org/0000-0003-1316-6483)
- Maria Virginia Ruiz Cuevas (ORCID: https://orcid.org/0000-0002-9974-264X)
- Anca Apavaloaei (ORCID: https://orcid.org/0000-0001-6896-1199)
- Mathieu Lajoie (ORCID: https://orcid.org/0000-0001-9162-086X)
- Mathieu Courcelles (ORCID: https://orcid.org/0000-0001-5961-8858)
- Ian Robert Watson (ORCID: https://orcid.org/0000-0002-6025-3080)
- Eralda Kina (ORCID: https://orcid.org/0000-0001-6191-7523)
- Grégory Ehx (ORCID: https://orcid.org/0000-0002-7018-1770)
- Claude Perreault (ORCID: https://orcid.org/0000-0001-9453-7383)
- Jean‐David Larouche (ORCID: https://orcid.org/0000-0003-3056-0714)
- Patrick Gendron (ORCID: https://orcid.org/0000-0001-9829-2600)
- Jean‐Philippe Laverdure (ORCID: https://orcid.org/0000-0002-9245-6413)
- M Cahuzac (ORCID: https://orcid.org/0000-0002-5395-8090)
- Julie Perrault
- Krystel Vincent (ORCID: https://orcid.org/0000-0001-6180-5345)
- Daniel E. Speiser (ORCID: https://orcid.org/0000-0003-2031-3250)
- Sébastien Lemieux (ORCID: https://orcid.org/0000-0001-5477-1386)
- Michal Bassani‐Sternberg (ORCID: https://orcid.org/0000-0002-1934-954X)
- Qingchuan Zhao (ORCID: https://orcid.org/0000-0003-4169-4945)
Institutions
- University of Liège (BE)
- Centre Hospitalier Universitaire Vaudois (CH)
- Institute for Research in Immunology and Cancer (CA)
- Ludwig Cancer Research (CH)
- Walloon Excellence in Lifesciences and Biotechnology (BE)
- McGill University (CA)
- Université de Montréal (CA)
- University of Lausanne (CH)
Publication Details
- Journal
- Nature Cancer
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1038/s43018-025-00979-2
- Citations
- 22
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 17.54
Funders
- Canadian Cancer Society Research Institute