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Updated: Jul 8, 2025
In Silico Identification and Characterization of circRNAs During Host-Pathogen Interactions
Published on: October 21, 2022
Tumour circular RNAs elicit anti-tumour immunity by encoding cryptic peptides
Di Huang1,2, Xiaofeng Zhu1,2, Shuying Ye1,2
1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Abstract:
Emerging data have shown that previously defined noncoding genomes might encode peptides that bind human leukocyte antigen (HLA) as cryptic antigens to stimulate adaptive immunity1,2. However, the significance and mechanisms of action of cryptic antigens in anti-tumour immunity remain unclear. Here mass spectrometry of the HLA class I (HLA-I) peptidome coupled with ribosome sequencing of human breast cancer samples identified HLA-I-binding cryptic antigenic peptides that were noncanonically translated by a tumour-specific circular RNA (circRNA): circFAM53B. The cryptic peptides efficiently primed naive CD4+ and CD8+ T cells in an antigen-specific manner and induced anti-tumour immunity. Clinically, the expression of circFAM53B and its encoded peptides was associated with substantial infiltration of antigen-specific CD8+ T cells and better survival in patients with breast cancer and patients with melanoma. Mechanistically, circFAM53B-encoded peptides had strong binding affinity to both HLA-I and HLA-II molecules. In vivo, administration of vaccines consisting of tumour-specific circRNA or its encoded peptides in mice bearing breast cancer tumours or melanoma induced enhanced infiltration of tumour-antigen-specific cytotoxic T cells, which led to effective tumour control. Overall, our findings reveal that noncanonical translation of circRNAs can drive efficient anti-tumour immunity, which suggests that vaccination exploiting tumour-specific circRNAs may serve as an immunotherapeutic strategy against malignant tumours.
Insights
Previously noncoding genomes can yield cryptic antigens from circular RNAs (circRNAs) that stimulate anti-tumor immunity. Tumor-specific circRNAs, like circFAM53B, can be harnessed for cancer vaccines to enhance T-cell responses and improve patient survival.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Previously noncoding genomic regions are now known to encode peptides that act as cryptic antigens, stimulating adaptive immunity.
- The precise role and mechanisms of cryptic antigens in anti-tumor immunity are not fully understood.
Purpose of the Study:
- To investigate the significance and mechanisms of cryptic antigens in anti-tumor immunity.
- To identify novel sources of cryptic antigens and evaluate their therapeutic potential in cancer.
Main Methods:
- Mass spectrometry of the HLA class I (HLA-I) peptidome and ribosome sequencing in human breast cancer samples.
- Identification and characterization of HLA-I-binding cryptic antigenic peptides derived from tumor-specific circular RNA (circRNA): circFAM53B.
- In vivo studies using circRNA or peptide vaccines in mouse models of breast cancer and melanoma.
Main Results:
- Identified HLA-I-binding cryptic peptides noncanonically translated by circFAM53B, which primed CD4+ and CD8+ T cells, inducing anti-tumor immunity.
- CircFAM53B expression correlated with increased antigen-specific CD8+ T-cell infiltration and improved survival in breast cancer and melanoma patients.
- Vaccination with circFAM53B or its peptides in mice enhanced tumor-antigen-specific cytotoxic T-cell infiltration, leading to effective tumor control.
Conclusions:
- Noncanonical translation of circRNAs can generate potent cryptic antigens that drive efficient anti-tumor immunity.
- Tumor-specific circRNAs represent a promising source for developing novel cancer immunotherapies and vaccines.
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