Immunopeptidomics-based identification of naturally presented non-canonical circRNA-derived peptides

Humberto J. Ferreira, Brian J. Stevenson, HuiSong Pak, Fengchao Yu, Jessica Almeida Oliveira, Florian Huber, Marie Taillandier-Coindard, Justine Michaux, Emma Ricart-Altimiras, Anne I. Kraemer, Lana E. Kandalaft, Daniel E. Speiser, Alexey I. Nesvizhskii, Markus Müller and Michal Bassani-Sternberg ()
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Humberto J. Ferreira: University of Lausanne
Brian J. Stevenson: University of Lausanne
HuiSong Pak: University of Lausanne
Fengchao Yu: University of Michigan
Jessica Almeida Oliveira: University of Lausanne
Florian Huber: University of Lausanne
Marie Taillandier-Coindard: University of Lausanne
Justine Michaux: University of Lausanne
Emma Ricart-Altimiras: University of Lausanne
Anne I. Kraemer: University of Lausanne
Lana E. Kandalaft: University of Lausanne
Daniel E. Speiser: Centre Hospitalier Universitaire Vaudois
Alexey I. Nesvizhskii: University of Michigan
Markus Müller: University of Lausanne
Michal Bassani-Sternberg: University of Lausanne

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Circular RNAs (circRNAs) are covalently closed non-coding RNAs lacking the 5’ cap and the poly-A tail. Nevertheless, it has been demonstrated that certain circRNAs can undergo active translation. Therefore, aberrantly expressed circRNAs in human cancers could be an unexplored source of tumor-specific antigens, potentially mediating anti-tumor T cell responses. This study presents an immunopeptidomics workflow with a specific focus on generating a circRNA-specific protein fasta reference. The main goal of this workflow is to streamline the process of identifying and validating human leukocyte antigen (HLA) bound peptides potentially originating from circRNAs. We increase the analytical stringency of our workflow by retaining peptides identified independently by two mass spectrometry search engines and/or by applying a group-specific FDR for canonical-derived and circRNA-derived peptides. A subset of circRNA-derived peptides specifically encoded by the region spanning the back-splice junction (BSJ) are validated with targeted MS, and with direct Sanger sequencing of the respective source transcripts. Our workflow identifies 54 unique BSJ-spanning circRNA-derived peptides in the immunopeptidome of melanoma and lung cancer samples. Our approach enlarges the catalog of source proteins that can be explored for immunotherapy.

Date: 2024
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DOI: 10.1038/s41467-024-46408-3

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