Multiomics prediction and immunogenic validation of personalized neoantigens in cholangiocarcinoma patients

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BACKGROUND: Cholangiocarcinoma (CCA) is an aggressive biliary tract cancer with limited treatment options, underscoring the need for breakthrough precision therapies. Neoantigen-based therapy is a promising novel strategy for cancer treatment. This study investigates the potential of neoantigen peptides in CCA, emphasizing their role in personalized immunotherapy and providing insights for vaccine design. METHODS: Paired samples from 33 CCA patients underwent whole-exome sequencing and RNA sequencing to profile the mutational and neoantigen landscape. Besides, personalized neoantigen peptides were synthesized and immunogenicity was validated through enzyme-linked immunospot assay. Meanwhile, corresponding T cell receptor (TCR) sequences were predicted by bioinformatics. RESULTS: TP53 was the most frequently mutated gene (57.58%) and a significant positive correlation between tumor mutational burden and neoantigen load was observed (r = 0.6511, p < 0.0001). A total of 798 neoantigens were identified in 22 samples, predominantly characterized by human leukocyte antigen (HLA) A02:07 and A02:01. Additionally, 16 neoantigen peptides from three CCA patients were successfully synthesized and these peptides induced robust T-cell responses, with the most potent epitopes derived from UBN1, C2orf47 and ITPR2. Moreover, bioinformatic analysis further predicted in silico putative TCR sequences potentially associated with the candidate neoantigens. In Pt01, the Vβ5-6Jβ1-2 sequence had the highest predicted affinity; in Pt02, the Vβ2Jβ1-4 sequence had the highest predicted affinity; and in Pt03, the Vβ29-1Jβ2-7 sequence had the highest predicted affinity. The sequence motifs of the high-frequency TCR clusters were also demonstrated. CONCLUSIONS: Our findings show that candidate immunogenic neoantigen peptides can be identified in CCA and are supported by proof-of-concept functional validation. Together, these results provide a framework for the downstream validation of neoantigen targets and the development of personalized immunotherapy approaches.

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