COSMIC-based mutation database enhances identification efficiency of HLA-I immunopeptidome

• Published in: Journal of translational medicine 2024-02, Vol.22 (1), p.144-16, Article 144
• Main Authors: Wang, Fanghzou, Zhang, Zhenpeng, Mao, Mingsong, Yang, Yudai, Xu, Ping, Lu, Shichun
• Format: Article
• Language: English
• Subjects: Antibodies; Antigens; Care and treatment; COSMIC database; Development and progression; Gene mutations; Genetic aspects; Genomes; Health aspects; Hepatocellular carcinoma; HepG2 cell; Histocompatibility antigen HLA; Histocompatibility antigens; HLA histocompatibility antigens; HLA immunopeptidome; Immunotherapy; Liver cancer; Lymphocytes T; Mass spectrometry; Mass spectroscopy; Medical prognosis; Mutants; Mutation; Neoantigen identification; Neoantigens; Patient outcomes; Peptides; Proteins; Scientific imaging; Testing; Tumors
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-023-04821-0

Neoantigens have emerged as a promising area of focus in tumor immunotherapy, with several established strategies aiming to enhance their identification. Human leukocyte antigen class I molecules (HLA-I), which present intracellular immunopeptides to T cells, provide an ideal source for identifying neoantigens. However, solely relying on a mutation database generated through commonly used whole exome sequencing (WES) for the identification of HLA-I immunopeptides, may result in potential neoantigens being missed due to limitations in sequencing depth and sample quality. In this study, we constructed and evaluated an extended database for neoantigen identification, based on COSMIC mutation database. This study utilized mass spectrometry-based proteogenomic profiling to identify the HLA-I immunopeptidome enriched from HepG2 cell. HepG2 WES-based and the COSMIC-based mutation database were generated and utilized to identify HepG2-specific mutant immunopeptides. The results demonstrated that COSMIC-based database identified 5 immunopeptides compared to only 1 mutant peptide identified by HepG2 WES-based database, indicating its effectiveness in identifying mutant immunopeptides. Furthermore, HLA-I affinity of the mutant immunopeptides was evaluated through NetMHCpan and peptide-docking modeling to validate their binding to HLA-I molecules, demonstrating the potential of mutant peptides identified by the COSMIC-based database as neoantigens. Utilizing the COSMIC-based mutation database is a more efficient strategy for identifying mutant peptides from HLA-I immunopeptidome without significantly increasing the false positive rate. HepG2 specific WES-based database may exclude certain mutant peptides due to WES sequencing depth or sample heterogeneity. The COSMIC-based database can effectively uncover potential neoantigens within the HLA-I immunopeptidomes.