Improving MHC-I Ligand Identifications from LC-MS/MS Data by Incorporating Allelic Peptide Motifs

MHC class I (MHC-I)-bound ligands play a pivotal role in CD8 T cell immunity and are hence of major interest in understanding and designing immunotherapies. One of the most commonly utilized approaches for detecting MHC ligands is LC-MS/MS. Unfortunately, the effectiveness of current algorithms to identify MHC ligands from LC-MS/MS data is limited because the search algorithms used were originally developed for proteomics approaches detecting tryptic peptides. Consequently, the analysis often results in inflated false discovery rate (FDR) statistics and an overall decrease in the number of peptides that pass FDR filters. Andreatta et al. describe a new scoring tool (MS-rescue) for peptides from MHC-I immunopeptidome datasets. MS-rescue incorporates the existence of MHC-I peptide motifs to rescore peptides from ligandome data. The tool is demonstrated here using peptides assigned from LC-MS/MS data with PEAKs software but can be deployed on data from any search algorithm. This new approach increased the number of peptides identified by up to 20–30% and promises to aid the discovery of novel MHC-I ligands with immunotherapeutic potential.