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Identification of tumor antigens with immunopeptidomics

Nature Biotechnology volume 40, pages 175–188 (2022)Cite this article

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Abstract

The identification of actionable tumor antigens is indispensable for the development of several cancer immunotherapies, including T cell receptor–transduced T cells and patient-specific mRNA or peptide vaccines. Most known tumor antigens have been identified through extensive molecular characterization and are considered canonical if they derive from protein-coding regions of the genome. By eluting human leukocyte antigen-bound peptides from tumors and subjecting these to mass spectrometry analysis, the peptides can be identified by matching the resulting spectra against reference databases. Recently, mass-spectrometry-based immunopeptidomics has enabled the discovery of noncanonical antigens—antigens derived from sequences outside protein-coding regions or generated by noncanonical antigen-processing mechanisms. Coupled with transcriptomics and ribosome profiling, this method enables the identification of thousands of noncanonical peptides, of which a substantial fraction may be detected exclusively in tumors. Spectral matching against the immense noncanonical reference may generate false positives. However, sensitive mass spectrometry, analytical validation and advanced bioinformatics solutions are expected to uncover the full landscape of presented antigens and clinically relevant targets.

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Fig. 1: The HLA-I processing and presentation pathway, along with the processes that can potentially generate noncanonical peptides.
Fig. 2: Noncanonical (and canonical) antigen identification and selection for immunotherapeutic applications, integrating information from multiple -omics levels and from publicly available datasets.
Fig. 3: Computational approaches to proteogenomics-directed immunopeptidomics analyses.

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Acknowledgements

This study was supported by the Ludwig Institute for Cancer Research and grant KFS-4680-02-2019-R from the Swiss Cancer League (M.B.-S.). This work was also supported by grants from Cancera, Mats Paulssons and by a gift from the Biltema Foundation that was administered by the ISREC Foundation, Lausanne, Switzerland. The figures were originally created with BioRender.com.

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Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Lausanne, Switzerland

    Chloe Chong, George Coukos & Michal Bassani-Sternberg

  2. Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

    Chloe Chong, George Coukos & Michal Bassani-Sternberg

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  1. Chloe Chong
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  2. George Coukos
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  3. Michal Bassani-Sternberg
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Correspondence to Michal Bassani-Sternberg.

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Chong, C., Coukos, G. & Bassani-Sternberg, M. Identification of tumor antigens with immunopeptidomics. Nat Biotechnol 40, 175–188 (2022). https://doi.org/10.1038/s41587-021-01038-8

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