Cytotoxic T-cell Neoepitopes of p53 Public Oncogenic Driver Mutations in Non-Small Cell Lung Cancer: Discovery via Integrative Computational Immunology
Leana Rich De Mesa Herrera-OngAbstract
Background:
Lung cancer is the leading cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) comprising 80% of cases. Despite advances in treatment, prognosis and 5-year survival rates remain poor. One of the most frequently mutated proteins in NSCLC is encoded by the tumor suppressor p53 (TP53), a neoantigen. The main objective of the study is to develop a workflow using immunoinformatics and databases to identify CD8+ neoepitopes from shared p53 driver mutations: R158L, R175H, Y220C, G245C, R248W, R273H, and R282W.
Methods:
Cytotoxic T-cell epitope mapping was conducted, excluding cross-reactive, allergenic, and toxic sequences. Neoepitopes were assessed for immunogenicity and agretopicity index, with validated epitopes used as references. Population coverage was estimated. Neoepitopes were docked with human leukocyte antigen I (HLA I) allele binders to calculate binding energy and dissociation constants. Immune simulations were also conducted.
Results:
Five neoepitopes – SVVVPCEPPEV, VVPCEPPEV, CACPGRDW, CMGGMNWR, and NWRPILTI – were identified with favorable safety profiles and broad population coverage. Agretopicity and binding strength analyses suggest HLA I can distinguish these from wild-type peptides.
Conclusion:
The candidate p53 neoepitopes are potentially immunogenic and safe with broad population coverage. It can be suitable for inclusion in future cancer vaccine ensembles targeting shared p53 mutations, with further