The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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Huang, D., Zhu, X., Ye, S. et al. Nature. 625, 593-602 (2024).
doi: 10.1038/s41586-023-06834-7.
Summary of the findings
Summary of the findingsImmunotherapy controls tumour progression by re-activating the anti-tumour immunity of cancer patients, which has developed rapidly and made revolutionary breakthroughs in malignancies such as melanoma and leukaemia. However, immunotherapy is less effective in solid tumours, which might be attributed to the lack of tumour-specific antigens (TSAs). Previous studies have mainly focused on nonsynonymous mutations in the protein-coding genome to identify TSAs. However, most solid tumours showed low mutational burden, which could not generate efficient neoantigens to elicit anti-tumor immunity.
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In this article, the authors identified TSAs derived from the open reading frames of tumour-specific circRNAs by matching the mass spectrometric analysis on human leukocyte antigen class I (HLA-I) immunoprecipitates of breast cancer tissues with whole-exome sequencing, RNA sequencing and ribosome sequencing data of tumour samples and their adjacent normal tissues. CircFAM53B, which encodes antigenic peptides distinct from its linear counterpart and bound to HLA-I, could elicit robust anti-tumour immune response in vitro and in patient-derived xenograft (PDX) mouse models. Moreover, vaccination with antigenic circRNA or its encoded cryptic antigenic peptides could effectively control the tumour growth and metastasis by eliciting strong antigen-specific immune responses in immunocompetent mice bearing breast cancer or melanoma. This research demonstrated that tumour-specific circRNAs are capable of eliciting anti-tumour immune responses by encoding cryptic antigenic peptides.
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Future impact
This research demonstrated that noncanonical translation of tumour-specific circRNAs are capable of eliciting anti-tumour immune responses at the initial step of priming tumour antigen-specific T cells and thereby enhance effector immune cell deployment, highlighting the therapeutic potential of vaccination exploiting tumour-specific circRNAs or their encoded cryptic antigenic peptides in malignant tumours.
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