Abstract

Background: Lung cancer in never-smokers is an increasingly prevalent and clinically distinct subtype of lung cancer, particularly in East Asian populations. Despite its rising incidence, there are currently no antigen-specific immunotherapeutic strategies or vaccines targeting lung cancer in never-smokers. This study aimed to identify and evaluate immunogenic epitopes derived from key oncogenic drivers in lung cancer in never-smokers as preliminary steps toward multi-epitope vaccine design.

Methods: Protein sequences of five lung cancer in never-smokers associated oncogenes (EGFR, KRAS, HER2, BRAF, and MET) were retrieved from UniProtKB and analyzed using a multi-tiered immunoinformatics workflow. B-cell, major histocompatibility complex class I, and major histocompatibility complex class II epitopes were predicted using tools such as NetMHCpan, NetMHCIIpan, and BepiPred. Candidate epitopes were identified based on HLA binding affinity, antigenicity (VaxiJen), toxicity, allergenicity while the ability of MHC-II epitopes to trigger the production of cytokines (IFN-γ, IL-4, IL-10) will be further assessed. Population coverage analysis was performed using the IEDB Population Coverage tool.

Results: Out of 1027 initial epitope predictions, only 16 epitopes (8 MHC-I, 4 MHC-II, and 4 B-cell epitopes) met all selection criteria. The final epitope exhibited strong antigenicity, HLA binding potential, and favorable global population coverage (81.23%). Several epitopes were highly specific to LCINS-related driver mutations, suggesting relevance for precision immunotherapy.

Conclusion: This study presents a rational, immunoinformatics-guided approach to identify and prioritize epitope candidates from lung cancer in never-smokers oncogenes. These findings provide a foundation for future design and preclinical evaluation of personalized multi-epitope cancer vaccines tailored to lung cancer in never-smokers.

Keywords: Lung cancer in never-smokers (LCINS); Immunoinformatics; Epitope prediction; Tumor-associated antigens; HLA binding and population coverage