A Novel Proteogenomic Integration Strategy Expands the Breadth of Neo-Epitope Sources
Tumor-specific antigens can activate T cell-based antitumor immune responses and are ideal targets for cancer immunotherapy. However, their identification is still challenging. Although mass spectrometry can directly identify human leukocyte antigen (HLA) binding peptides in tumor cells, it focuses...
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Published in | Cancers Vol. 14; no. 12; p. 3016 |
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Abstract | Tumor-specific antigens can activate T cell-based antitumor immune responses and are ideal targets for cancer immunotherapy. However, their identification is still challenging. Although mass spectrometry can directly identify human leukocyte antigen (HLA) binding peptides in tumor cells, it focuses on tumor-specific antigens derived from annotated protein-coding regions constituting only 1.5% of the genome. We developed a novel proteogenomic integration strategy to expand the breadth of tumor-specific epitopes derived from all genomic regions. Using the colorectal cancer cell line HCT116 as a model, we accurately identified 10,737 HLA-presented peptides, 1293 of which were non-canonical peptides that traditional database searches could not identify. Moreover, we found eight tumor neo-epitopes derived from somatic mutations, four of which were not previously reported. Our findings suggest that this new proteogenomic approach holds great promise for increasing the number of tumor-specific antigen candidates, potentially enlarging the tumor target pool and improving cancer immunotherapy. |
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AbstractList | Tumor-specific antigens can activate T cell-based antitumor immune responses and are ideal targets for cancer immunotherapy. However, their identification is still challenging. Although mass spectrometry can directly identify human leukocyte antigen (HLA) binding peptides in tumor cells, it focuses on tumor-specific antigens derived from annotated protein-coding regions constituting only 1.5% of the genome. We developed a novel proteogenomic integration strategy to expand the breadth of tumor-specific epitopes derived from all genomic regions. Using the colorectal cancer cell line HCT116 as a model, we accurately identified 10,737 HLA-presented peptides, 1293 of which were non-canonical peptides that traditional database searches could not identify. Moreover, we found eight tumor neo-epitopes derived from somatic mutations, four of which were not previously reported. Our findings suggest that this new proteogenomic approach holds great promise for increasing the number of tumor-specific antigen candidates, potentially enlarging the tumor target pool and improving cancer immunotherapy. Simple SummaryTumor-specific antigens are ideal targets for cancer immunotherapy. Mass spectrometry, which is the main method that directly identifies neo-epitopes presented on tumor cells, focuses mainly on peptides derived from annotated protein-coding exomes. However, non-canonical peptides arising from alterations at genomic, transcriptional, and posttranslational levels have been identified in several pioneering studies, making it necessary to develop an integrated proteogenomic approach that can comprehensively identify neoantigens derived from all genomic regions. Our novel strategy combining database searches with a de novo peptide sequencing method accurately identified multiple types of non-canonical peptides in the colorectal cancer cell line, HCT116. This practical proteogenomic strategy can be applied to neoantigen discovery in clinical tumor samples, improving cancer immunotherapy.AbstractTumor-specific antigens can activate T cell-based antitumor immune responses and are ideal targets for cancer immunotherapy. However, their identification is still challenging. Although mass spectrometry can directly identify human leukocyte antigen (HLA) binding peptides in tumor cells, it focuses on tumor-specific antigens derived from annotated protein-coding regions constituting only 1.5% of the genome. We developed a novel proteogenomic integration strategy to expand the breadth of tumor-specific epitopes derived from all genomic regions. Using the colorectal cancer cell line HCT116 as a model, we accurately identified 10,737 HLA-presented peptides, 1293 of which were non-canonical peptides that traditional database searches could not identify. Moreover, we found eight tumor neo-epitopes derived from somatic mutations, four of which were not previously reported. Our findings suggest that this new proteogenomic approach holds great promise for increasing the number of tumor-specific antigen candidates, potentially enlarging the tumor target pool and improving cancer immunotherapy. |
Author | Zhang, Le Gu, Ying Chen, Lei Xiang, Haitao Bu, Fanyu Zhang, Weicong Zhao, Yuntong Hou, Yong Mei, Zhanlong Rao, Yuan Dong, Xuan Chen, Huanyi Lee, Leo Jingyu Guan, Xiangyu Mu, Feng Zhang, Haibo Li, Yijian |
AuthorAffiliation | 2 BGI-Shenzhen, Shenzhen 518103, China; bufanyu@genomics.cn (F.B.); aloha.chenlei@gmail.com (L.C.); zhanghaibo3@genomics.cn (H.Z.); zhaoyuntong@genomics.cn (Y.Z.); chenhuanyi@genomics.cn (H.C.); guying@genomics.cn (Y.G.) 4 Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen 518083, China 1 College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; xianghaitao@genomics.cn (H.X.); guanxiangyu@genomics.cn (X.G.); zhangweicong@genomics.cn (W.Z.); liyijian@genomics.cn (Y.L.) 6 Guangdong Provincial Key Laboratory of Genome Read and Write, Shenzhen 518120, China 5 BGI, Shenzhen 518083, China; meizhanlong@genomics.cn (Z.M.); raoyuan@genomics.cn (Y.R.); houyong@mgi-tech.com (Y.H.) 3 BGI-GenoImmune, BGI-Shenzhen, Shenzhen 518083, China; zhangle@genomics.cn (L.Z.); leeleojingyu@genomics.cn (L.J.L.) |
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Snippet | Tumor-specific antigens can activate T cell-based antitumor immune responses and are ideal targets for cancer immunotherapy. However, their identification is... Simple SummaryTumor-specific antigens are ideal targets for cancer immunotherapy. Mass spectrometry, which is the main method that directly identifies... |
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SubjectTerms | Antigen (tumor-associated) Antigens Antitumor activity Cancer Cancer immunotherapy Colorectal cancer Colorectal carcinoma Epitopes Genomes Genomics Histocompatibility antigen HLA Immunotherapy Integrated approach Integration Lymphocytes T Mass spectrometry Mass spectroscopy Melanoma Mutation Neoantigens Peptides Scientific imaging Tumor cells |
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Title | A Novel Proteogenomic Integration Strategy Expands the Breadth of Neo-Epitope Sources |
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