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41237784
Predominant mutated non-canonical tumor-specific antigens identified by proteogenomics demonstrate immunogenicity and tumor suppression in CRC.

Cell Genom, 2026/1/14;6(1):101062.

Xiang H[1], Guan X[2], Wei Y[3], Luo S[4], Zhang H[2], Bu F[5], Yan Y[5], Fu Y[2], Li Y[6], Xu Q[7], Lin P[4], Liu D[4], Zhou X[8], Gao F[9], Chen T[10], Nie G[11], Wu K[12], Gu Y[6], Liu L[7], Ye Z[13], Wu X[14], Zhao R[15], Liu S[16], Dong X[17]

Affiliations

PMID: 41237784DOI: 10.1016/j.xgen.2025.101062

Abstract
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+ 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.

Keywords: colorectal cancer; immunopeptidome; immunotherapy; neo-epitope; proteogenomics; tumor-specific antigens

MeSH terms
Proteogenomics; Humans; Colorectal Neoplasms; Animals; Antigens, Neoplasm; Mice; Mutation; CD8-Positive T-Lymphocytes; Female; Male; Mice, Inbred C57BL
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