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Immunopeptidomics: Isolation of Mouse and Human MHC Class I- and II-Associated Peptides for Mass Spectrometry Analysis
Published on: October 15, 2021
Identification of tumor antigens with immunopeptidomics
Chloe Chong1,2, George Coukos1,2, Michal Bassani-Sternberg3,4
1Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Lausanne, Switzerland.
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.
Insights
Identifying novel tumor antigens is crucial for cancer immunotherapy development. Mass spectrometry-based immunopeptidomics reveals noncanonical antigens, expanding the scope of potential therapeutic targets.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Actionable tumor antigens are essential for developing cancer immunotherapies like T cell therapies and vaccines.
- Canonical tumor antigens are typically derived from protein-coding genomic regions.
- Current methods rely on mass spectrometry to identify peptides bound to human leukocyte antigen (HLA).
Purpose of the Study:
- To explore the discovery of noncanonical tumor antigens using mass spectrometry-based immunopeptidomics.
- To identify novel antigens derived from non-protein-coding regions or via noncanonical processing.
- To assess the potential of these antigens for cancer immunotherapy.
Main Methods:
- Eluting human leukocyte antigen-bound peptides from tumors.
- Mass spectrometry analysis of eluted peptides.
- Matching spectra against reference databases, including noncanonical sequences.
- Integration with transcriptomics and ribosome profiling.
Main Results:
- Mass spectrometry-based immunopeptidomics enables the discovery of noncanonical antigens.
- Thousands of noncanonical peptides can be identified, some exclusively in tumors.
- Challenges include potential false positives from spectral matching against extensive noncanonical databases.
Conclusions:
- Noncanonical antigens represent a significant, largely untapped resource for cancer immunotherapy.
- Advanced analytical validation and bioinformatics are key to overcoming challenges and realizing the potential of these targets.
- The full landscape of presented antigens and clinically relevant targets is expected to be uncovered with further research.
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