Predominant mutated non-canonical tumor-specific antigens identified by proteogenomics demonstrate immunogenicity and tumor suppression in CRC
Tumor-specific antigens (TSAs) are crucial for activating T cells against cancer, but traditional discovery methods focusing on exonic mutations overlook non-canonical TSAs from non-coding regions. We employed an integrative proteogenomic strategy combining whole-genome and RNA sequencing with immunoprecipitation mass spectrometry to comprehensively explore TSA generation in colorectal cancer patients. Analysis of 10 paired tumor samples identified 96 mutated major histocompatibility complex class I-presented neo-epitopes, with 80.21% originating from non-coding regions. In hypermutated tumors with high mutational burden, neo-epitopes predominantly arose from intergenic and intronic areas, while in non-hypermutated tumors with low mutational burden, they mainly stemmed from coding variations and alternative splicing events. Functional validation in mouse models demonstrated that mutated non-canonical neo-epitopes effectively activated CD8<sup>+</sup> T cells and significantly suppressed tumor growth. These findings underscore the importance of considering the entire genomic landscape in TSA discovery, suggesting new avenues for personalized immunotherapy.
Authors
- Penghui Lin (ORCID: https://orcid.org/0000-0002-0534-625X)
- Ruifang Zhao (ORCID: https://orcid.org/0000-0002-2735-2159)
- Qumiao Xu
- Kui Wu (ORCID: https://orcid.org/0000-0002-6857-7231)
- Yaohua Wei (ORCID: https://orcid.org/0000-0001-9388-2900)
- Longqi Liu (ORCID: https://orcid.org/0000-0002-5828-5542)
- Fanyu Bu (ORCID: https://orcid.org/0000-0002-0875-7708)
- Dongbing Liu (ORCID: https://orcid.org/0000-0003-2870-5187)
- Xinlan Zhou (ORCID: https://orcid.org/0000-0001-9293-0894)
- Feng Gao (ORCID: https://orcid.org/0000-0002-1825-328X)
- Guangjun Nie (ORCID: https://orcid.org/0000-0001-5040-9793)
- Yijian Li (ORCID: https://orcid.org/0000-0002-7619-8207)
- Xuan Dong (ORCID: https://orcid.org/0000-0001-8288-322X)
- Yunyun Fu
- Ziqing Ye (ORCID: https://orcid.org/0000-0002-6588-2839)
- Haitao Xiang (ORCID: https://orcid.org/0000-0001-9971-1715)
- Siqi Liu (ORCID: https://orcid.org/0000-0001-9744-3681)
- Haibo Zhang (ORCID: https://orcid.org/0000-0003-3796-5095)
- Tai Chen
- Xiaojian Wu (ORCID: https://orcid.org/0000-0001-5610-2530)
- Ying Gu (ORCID: https://orcid.org/0000-0001-6059-7361)
- Yixin Yan (ORCID: https://orcid.org/0000-0003-4167-9745)
- Xiangyu Guan (ORCID: https://orcid.org/0000-0001-9396-8245)
- Shuzhen Luo
Institutions
- BGI Group (China) (CN)
- Sun Yat-sen University (CN)
- Sixth Affiliated Hospital of Sun Yat-sen University (CN)
- Zhejiang Cancer Hospital (CN)
- Zhejiang Hospital (CN)
- National Center for Nanoscience and Technology (CN)
- University of Chinese Academy of Sciences (CN)
- Hangzhou Cancer Hospital (CN)
- BGI Research (CN)
Publication Details
- Journal
- Cell Genomics
- Published
- 2025-11-13
- DOI
- https://doi.org/10.1016/j.xgen.2025.101062
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00