Although mutations may represent attractive targets for immunotherapy, direct identification of mutated peptide ligands isolated from human leucocyte antigens (HLA) on the surface of native tumour tissue has so far not been successful. Using advanced mass spectrometry (MS) analysis, we survey the melanoma-associated immunopeptidome to a depth of 95,500 patient-presented peptides. We thereby discover a large spectrum of attractive target antigen candidates including cancer testis antigens and phosphopeptides. Most importantly, we identify peptide ligands presented on native tumour tissue samples harbouring somatic mutations. Four of eleven mutated ligands prove to be immunogenic by neoantigen-specific T-cell responses. Moreover, tumour-reactive T cells with specificity for selected neoantigens identified by MS are detected in the patient’s tumour and peripheral blood. We conclude that direct identification of mutated peptide ligands from primary tumour material by MS is possible and yields true neoepitopes with high relevance for immunotherapeutic strategies in cancer. Neoantigens determine anti-cancer immunoreactivity and are important functional targets for immunotherapy. Here, the authors use deep mass spectrometry to characterize neoepitopes from human melanoma tissue and show the presence of tumour-reactive T cells with specificity for selected neoantigens.
Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry
M. Bassani-Sternberg,E. Bräunlein,R. Klar,T. Engleitner,Pavel Sinitcyn,S. Audehm,M. Straub,Julia Weber,J. Slotta-Huspenina,K. Specht,M. Martignoni,A. Werner,R. Hein,Dirk H. Busch,C. Peschel,R. Rad,J. Cox,M. Mann,A. Krackhardt
Published 2016 in Nature Communications
ABSTRACT
PUBLICATION RECORD
- Publication year
2016
- Venue
Nature Communications
- Publication date
2016-11-21
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- advanced mass spectrometry
A high-sensitivity mass spectrometry workflow used to identify HLA-presented peptides from melanoma tissue.
Aliases: MS
- cancer testis antigens
A class of tumour-associated antigens normally restricted to germline tissues and aberrantly expressed in cancers.
- melanoma-associated immunopeptidome
The collection of peptides presented by HLA molecules in melanoma samples.
- mutated peptide ligands
HLA-bound peptide ligands that contain amino-acid changes arising from somatic mutation.
Aliases: mutated ligands
- native tumour tissue
Unmanipulated primary melanoma specimens used as the source material for peptide isolation.
- neoantigens
Mutation-derived peptide antigens that can be presented to the immune system.
Aliases: neoepitopes
- neoantigen-specific t-cell responses
T-cell reactivity directed against peptides derived from tumour-specific mutations.
- patient-presented peptides
Peptides identified directly from individual patient samples as part of the HLA-bound peptide pool.
- phosphopeptides
Peptides containing phosphorylated residues that can be presented by HLA molecules.
- somatic mutations
Acquired DNA alterations in tumour cells that can change encoded peptide sequences.
- tumour-reactive t cells
T cells that recognize antigens associated with the patient’s tumour.
REFERENCES
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