Deciphering the MHC immunopeptidome of human cancers with Ligand.MHC atlas

A fundamental principle of immunotherapy is that T cells are capable of detecting tumor epitopes presented on cancer cell surfaces. Immunopeptidomic strategies empowered by liquid chromatography-tandem mass spectrometry have transformed tumor epitopes identification and provided novel insights into tumor immunology. It enables in-depth profiling of major histocompatibility complex (MHC) presented ligands, thereby offering valuable perspectives on the molecular dialog among tumor and T cells. Here, we developed an immune-ligand identification and analysis pipeline from large-scale immunopeptidomics data. Through an extensive collection and processing of 5821 immunopeptidomic samples, which amounted to 305.7 million MS2 spectra, we identified 24 380 595 peptide-spectrum matches from these samples and further detected a total of 1 017 731 unique MHC immune ligands. These ligands were deconvolved and classified to specific HLA alleles. In total, we detected 582 852 HLA-I peptides and 434 879 HLA-II peptides that can bind to 292 HLA alleles, thereby greatly expanding the cancer immunopeptidome. Additionally, we identified and annotated 372 720 tumor-associated post-translational modification (PTM) peptides, revealing the comprehensive landscape of PTM antigens. All ligands and annotations were aggregated into Ligand.MHC Atlas, a comprehensive repository dedicated to tumor-derived HLA-presented ligands across 26 major human cancers (54 subtypes). Overall, our study uniquely integrates batch-effect correction, leverages the optimized software with novel deconvolution approach for immunopeptidomics analysis and ligand identification, and provides a public web portal with a comprehensive HLA ligand repository. Ligand.MHC Atlas functions as an invaluable resource, offering crucial understandings into immunology investigations. It will accelerate the advancement of cancer vaccines and immunotherapies. Ligand.MHC Atlas is available at http://modinfor.com/Ligand.MHC-Atlas/.