Predominant mutated non-canonical tumor-specific antigens identified by proteogenomics demonstrate immunogenicity and tumor suppression in CRC
(1) Xiang H (2) Guan X (3) Wei Y (4) Luo S (5) Zhang H (6) Bu F (7) Yan Y (8) Fu Y (9) Li Y (10) Xu Q (11) Lin P (12) Liu D (13) Zhou X (14) Gao F (15) Chen T (16) Nie G (17) Wu K (18) Gu Y (19) Liu L (20) Ye Z (21) Wu X (22) Zhao R (23) Liu S (24) Dong X
Xiang et al. integrated whole-genome, transcriptomics, and MHC-I immunopeptidomics analyses to identify tumor-specific antigens from non-coding regions in colorectal cancer samples. Across 10 paired samples, over 80% of 96 MHC-I-presented neo-epitopes originated from intergenic and intronic regions. Hypermutated tumors showed the highest burden of non-canonical neo-epitopes, while non-hypermutated tumors relied on coding alterations and alternative splicing. In the subcutaneous MC38 model, multi-epitope vaccines containing mutated non-canonical neo-epitopes effectively activated CD8+ T cells and suppressed tumor growth in a CD8+ T cell-dependent manner.
Contributed by Shishir Pant
(1) Xiang H (2) Guan X (3) Wei Y (4) Luo S (5) Zhang H (6) Bu F (7) Yan Y (8) Fu Y (9) Li Y (10) Xu Q (11) Lin P (12) Liu D (13) Zhou X (14) Gao F (15) Chen T (16) Nie G (17) Wu K (18) Gu Y (19) Liu L (20) Ye Z (21) Wu X (22) Zhao R (23) Liu S (24) Dong X
Xiang et al. integrated whole-genome, transcriptomics, and MHC-I immunopeptidomics analyses to identify tumor-specific antigens from non-coding regions in colorectal cancer samples. Across 10 paired samples, over 80% of 96 MHC-I-presented neo-epitopes originated from intergenic and intronic regions. Hypermutated tumors showed the highest burden of non-canonical neo-epitopes, while non-hypermutated tumors relied on coding alterations and alternative splicing. In the subcutaneous MC38 model, multi-epitope vaccines containing mutated non-canonical neo-epitopes effectively activated CD8+ T cells and suppressed tumor growth in a CD8+ T cell-dependent manner.
Contributed by Shishir Pant
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.
Author Info:
(1) HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou 310000, China; BGI Research, Hangzhou 310030,
China; BGI Research, Shenzhen 518083, China. (2) HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou 310000, China; BGI Research, Hangzhou 310030, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. (3) National Center for Nanoscience and Technology, Beijing 100190, China. (4) HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou 310000, China; BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, BGI Research, Shenzhen 518083, China. (5) HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou 310000, China; BGI Research, Hangzhou 310030, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. (6) HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou 310000, China; BGI Research, Hangzhou 310030, China. (7) HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou 310000, China; BGI Research, Hangzhou 310030, China. (8) HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou 310000, China; BGI Research, Hangzhou 310030, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. (9) BGI Research, Shenzhen 518083, China. (10) BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China. (11) HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou 310000, China; BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, BGI Research, Shenzhen 518083, China. (12) HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou 310000, China; BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, BGI Research, Shenzhen 518083, China. (13) HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou 310000, China; BGI Research, Shenzhen 518083, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, BGI Research, Shenzhen 518083, China. (14) The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, China. (15) BGI Research, Shenzhen 518083, China; BGI Research, Changzhou 213299, China; Guangdong Provincial Key Laboratory of Genome Read and Write, BGl-Shenzhen, Shenzhen 518120, China. (16) National Center for Nanoscience and Technology, Beijing 100190, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (17) HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou 310000, China; BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, BGI Research, Shenzhen 518083, China. (18) BGI Research, Shenzhen 518083, China. (19) BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China. (20) Zhejiang Hospital, Hangzhou 310013, China. Electronic address: yzq2229@163.com. (21) The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, China. Electronic address: wuxjian@mail.sysu.edu.cn. (22) National Center for Nanoscience and Technology, Beijing 100190, China; Guangdong Provincial Key Laboratory of Genome Read and Write, BGl-Shenzhen, Shenzhen 518120, China. Electronic address: zhaorf@nanoctr.cn. (23) HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou 310000, China; BGI, Shenzhen 518083, China. Electronic address: siqiliu@genomics.cn. (24) HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou 310000, China; BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, BGI Research, Shenzhen 518083, China. Electronic address: dongxuan@genomcs.cn.
Citation: Cell Genom 2025 Nov 13 101062 Epub11/13/2025
