Tumor-Specific CircRNA-Derived Antigen Peptide Identification for Hepatobiliary Tumors

Engineering ›› 2023, Vol. 22 ›› Issue (3) : 159 -170. DOI: 10.1016/j.eng.2022.06.008

Research

Article

Wenwen Wang ^a^,^*
, Lili Ma ^b^,^c^,^*
, Zheng Xing ^b^,^c^,^*
, Tinggan Yuan ^b^,^c^,^d
, Jinxia Bao ^e^,^f
, Yanjing Zhu ^g^,^h
, Xiaofang Zhao ^a
, Yan Zhao ⁱ
, Yali Zong ⁱ
, Yani Zhang ⁱ
, Siyun Shen ^g^,^h
, Xinyao Qiu ^a
, Shuai Yang ^a
, Hongyang Wang ^a^,^g^,^h
, Dong Gao ^c^,^j^,^k
, Peng Wang ^b^,^c^,^l
, Lei Chen ^a^,^h^,^m

Author information +

^a Fudan University Shanghai Cancer Center, Shanghai 200032, China

^b Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China

^c University of Chinese Academy of Sciences, Beijing 100049, China

^d School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China

^e State Key Laboratory of Pharmaceutical Biotechnology & Model Animal Research Center of Nanjing University and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China

^f School of Medicine, Nanjing University, Nanjing 210093, China

^g The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China

^h National Center for Liver Cancer, Shanghai 200441, China

ⁱ Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200433, China

^j State Key Laboratory of Cell Biology & Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China

^k Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China

^l Faculty of Health Sciences, University of Macau, Macao 999078, China

^m Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education & Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China

^* These authors contributed equally to this work.

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History +

Received	Accepted	Published
2022-03-18		2023-01-24
Issue Date	Revised Date
2024-06-13

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Abstract

The application of tumor antigen-based immunotherapy is hindered by the rarity of validated immunogenic peptides. In this study, we aimed to investigate the potential of circular RNAs (circRNAs) as a novel source of tumor antigen peptides in hepatobiliary tumor organoids. Using RNA-sequencing (RNA-seq) with an algorithm-based score tool, 3950 translated tumor-specific circRNAs were predicted to generate 18 971 antigen peptides in 27 organoids. In view of the antigen landscape, 11 amino acid length (mer) peptides and human leukocyte antigen (HLA)-A binding peptides harbored the highest immunogenicity-related scores. In three out of five analyzed organoids, 13 predicted antigen peptides were directly confirmed as HLA-A, -B, and -C (HLA-ABC) binding peptides with mass spectrometry (MS)-based immunopeptidomics. CircRNA-derived tumor-specific peptides presented by the HLA-ABC molecules stimulated cluster of differentiation 8 (CD8) T cells to exhibit increased CD107a interferon γ (IFNγ) co-expressions and IFNγ secretion in flow cytometry and enzyme-linked immunosorbent assay (ELISA). Cytotoxic T cell activity targeting the organoids, induced by the immunogenic circRNA-derived peptides, was verified in a killing assay. Notably, the antigen peptide YGFNEILKK from circTBC1D15 was not only recognized as an HLA-ABC-presented peptide of the organoids but also drastically reduced the tumor organoid survival rate. Our findings highlight a crucial subset for generating tumor antigens, which has implications for targeting tumor-specific circRNAs in cancers.

Keywords

Tumor antigen / Patient-derived hepatobiliary tumor organoid / Circular RNA / Mass-spectrometry-based immunopeptidomics

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Wenwen Wang, Lili Ma, Zheng Xing, Tinggan Yuan, Jinxia Bao, Yanjing Zhu, Xiaofang Zhao, Yan Zhao, Yali Zong, Yani Zhang, Siyun Shen, Xinyao Qiu, Shuai Yang, Hongyang Wang, Dong Gao, Peng Wang, Lei Chen. Tumor-Specific CircRNA-Derived Antigen Peptide Identification for Hepatobiliary Tumors. Engineering, 2023, 22(3): 159-170 DOI:10.1016/j.eng.2022.06.008