BACKGROUND: 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. METHOD: 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. RESULT: 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. CONCLUSION: 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.
Author Info:
(1) Medical School of Chinese People's Liberation Army (PLA), Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Institute of Hepatobiliary Surgery of Chine
se PLA, Key Laboratory of Digital Hepatobiliary Surgery PLA, 28 Fuxing Road, Haidian District, Beijing, 100853, China. (2) State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Research Unit of Proteomics and Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Proteome Research Center, Institute of Lifeomics, 38 Life Science Park Road, Changping District, Beijing, 102206, China. (3) State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Research Unit of Proteomics and Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Proteome Research Center, Institute of Lifeomics, 38 Life Science Park Road, Changping District, Beijing, 102206, China. School of Basic Medical Sciences, Anhui Medical University, Hefei, China. (4) State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Research Unit of Proteomics and Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Proteome Research Center, Institute of Lifeomics, 38 Life Science Park Road, Changping District, Beijing, 102206, China. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. (5) State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Research Unit of Proteomics and Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Proteome Research Center, Institute of Lifeomics, 38 Life Science Park Road, Changping District, Beijing, 102206, China. xuping@ncpsb.org.cn. School of Basic Medical Sciences, Anhui Medical University, Hefei, China. xuping@ncpsb.org.cn. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. xuping@ncpsb.org.cn. School of Medicine, Guizhou University, Guiyang, China. xuping@ncpsb.org.cn. (6) Medical School of Chinese People's Liberation Army (PLA), Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Institute of Hepatobiliary Surgery of Chinese PLA, Key Laboratory of Digital Hepatobiliary Surgery PLA, 28 Fuxing Road, Haidian District, Beijing, 100853, China. lusc_301@163.com.
Citation: J Transl Med 2024 Feb 10 22:144 Epub02/10/2024
