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Multiomics prediction and immunogenic validation of personalized neoantigens in cholangiocarcinoma patients
Baoluhe Zhang1, Bao Jin1, Xueshuai Wan1
1Department of Liver Surgery, State Key Laboratory of Common Mechanism Research for Major Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Wangfujing, Beijing, 100730, China.
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.
Insights
This study identifies immunogenic neoantigen peptides in cholangiocarcinoma (CCA), a rare cancer. These findings support developing personalized immunotherapy and vaccines for CCA patients.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Cholangiocarcinoma (CCA) is an aggressive cancer with limited treatment options.
- Neoantigen-based therapy offers a promising avenue for precision cancer treatment.
- This research explores neoantigen peptides for personalized immunotherapy in CCA.
Purpose of the Study:
- To investigate the potential of neoantigen peptides in cholangiocarcinoma (CCA).
- To identify neoantigens for personalized immunotherapy and vaccine design in CCA.
- To validate the immunogenicity of candidate neoantigen peptides.
Main Methods:
- Whole-exome and RNA sequencing of 33 CCA patient samples.
- Identification and synthesis of personalized neoantigen peptides.
- Enzyme-linked immunospot assay for immunogenicity validation and T-cell receptor (TCR) prediction.
Main Results:
- TP53 mutation was frequent (57.58%); tumor mutational burden correlated with neoantigen load.
- 798 neoantigens were identified, with HLA-A02:07 and HLA-A02:01 being predominant.
- Synthesized peptides induced robust T-cell responses, with UBN1, C2orf47, and ITPR2 as potent epitopes.
Conclusions:
- Immunogenic neoantigen peptides can be identified in CCA.
- Functional validation supports these neoantigen targets for immunotherapy.
- Provides a framework for developing personalized neoantigen-based therapies for CCA.
