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 inCancers Vol. 14; no. 12; p. 3016
Main Authors Xiang, Haitao, Zhang, Le, Bu, Fanyu, Guan, Xiangyu, Chen, Lei, Zhang, Haibo, Zhao, Yuntong, Chen, Huanyi, Zhang, Weicong, Li, Yijian, Lee, Leo Jingyu, Mei, Zhanlong, Rao, Yuan, Gu, Ying, Hou, Yong, Mu, Feng, Dong, Xuan
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Published Basel MDPI AG 19.06.2022
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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.
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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– name: 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.)
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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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proquest
crossref
SourceType Open Access Repository
Aggregation Database
StartPage 3016
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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Volume 14
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