Tumour circular RNAs elicit anti-tumour immunity by encoding cryptic peptides

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.