Journal
PROTEOMICS
Volume 16, Issue 10, Pages 1570-1580Publisher
WILEY
DOI: 10.1002/pmic.201500445
Keywords
Biomedicine; HLA class I; Immunopeptidomics; Melanoma; sHLA tumor-associated epitopes
Funding
- European Union [305309, 305608]
- ETH Zurich
- Swiss National Science Foundation (SNF)
- Bovena Foundation
- Majores Foundation
- European Research Council (ERC Advanced Grant Zauberkugel)
- Swiss Federal Institute of Technology Zurich (ETHZ)
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The characterization of peptides bound to human leukocyte antigen (HLA) class I is of fundamental importance for understanding CD8+ T cell-driven immunological processes and for the development of immunomodulatory therapeutic strategies. However, until now, the mass spectrometric analysis of HLA-bound peptides has typically required billions of cells, still resulting in relatively few high-confidence peptide identifications. Capitalizing on the recent developments in mass spectrometry and bioinformatics, we have implemented a methodology for the efficient recovery of acid-eluted HLA peptides after purification with the pan-reactive antibody W6/32 and have identified a total of 27 862 unique peptides with high confidence (1% false discovery rate) from five human cancer cell lines. More than 93% of the identified peptides were eight to 11 amino acids in length and contained signatures that were in excellent agreement with published HLA binding motifs. Furthermore, by purifying soluble HLA class I complexes (sHLA) from sera of melanoma patients, up to 972 high-confidence peptides could be identified, including melanoma-associated antigens already described in the literature. Knowledge of the HLA class I peptidome should facilitate multiplex tetramer technology-based characterization of T cells, and allow the development of patient selection, stratification and immunomodulatory therapeutic strategies.
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