Anti-tumour immunity induces aberrant peptide presentation in melanoma

Osnat Bartok, Abhijeet Pataskar, Remco Nagel, Maarja Laos, Eden Goldfarb, Deborah Hayoun, Ronen Levy, Pierre-Rene Körner, Inger Z. M. Kreuger, Julien Champagne, Esther A. Zaal, Onno B. Bleijerveld, Xinyao Huang, Juliana Kenski, Jennifer Wargo, Alexander Brandis, Yishai Levin, Orel Mizrahi, Michal Alon, Sacha Lebon, Weiwen Yang, Morten M. Nielsen, Noam Stern-Ginossar, Maarten Altelaar, Celia R. Berkers, Tamar Geiger, Daniel S. Peeper, Johanna Olweus, Yardena Samuels () and Reuven Agami ()
Additional contact information
Osnat Bartok: Weizmann Institute of Science
Abhijeet Pataskar: The Netherlands Cancer Institute
Remco Nagel: The Netherlands Cancer Institute
Maarja Laos: Oslo University Hospital Radiumhospitalet
Eden Goldfarb: Weizmann Institute of Science
Deborah Hayoun: Weizmann Institute of Science
Ronen Levy: Weizmann Institute of Science
Pierre-Rene Körner: The Netherlands Cancer Institute
Inger Z. M. Kreuger: The Netherlands Cancer Institute
Julien Champagne: The Netherlands Cancer Institute
Esther A. Zaal: Utrecht University and Netherlands Proteomics Centre
Onno B. Bleijerveld: Proteomics Facility, The Netherlands Cancer Institute
Xinyao Huang: The Netherlands Cancer Institute
Juliana Kenski: The Netherlands Cancer Institute
Jennifer Wargo: The University of Texas MD Anderson Cancer Center
Alexander Brandis: Weizmann Institute of Science
Yishai Levin: Weizmann Institute of Science
Orel Mizrahi: Weizmann Institute of Science
Michal Alon: Weizmann Institute of Science
Sacha Lebon: Weizmann Institute of Science
Weiwen Yang: Oslo University Hospital Radiumhospitalet
Morten M. Nielsen: Oslo University Hospital Radiumhospitalet
Noam Stern-Ginossar: Weizmann Institute of Science
Maarten Altelaar: Utrecht University and Netherlands Proteomics Centre
Celia R. Berkers: Utrecht University and Netherlands Proteomics Centre
Tamar Geiger: Sackler School of Medicine
Daniel S. Peeper: The Netherlands Cancer Institute
Johanna Olweus: Oslo University Hospital Radiumhospitalet
Yardena Samuels: Weizmann Institute of Science
Reuven Agami: The Netherlands Cancer Institute

Nature, 2021, vol. 590, issue 7845, 332-337

Abstract: Abstract Extensive tumour inflammation, which is reflected by high levels of infiltrating T cells and interferon-γ (IFNγ) signalling, improves the response of patients with melanoma to checkpoint immunotherapy1,2. Many tumours, however, escape by activating cellular pathways that lead to immunosuppression. One such mechanism is the production of tryptophan metabolites along the kynurenine pathway by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which is induced by IFNγ3–5. However, clinical trials using inhibition of IDO1 in combination with blockade of the PD1 pathway in patients with melanoma did not improve the efficacy of treatment compared to PD1 pathway blockade alone6,7, pointing to an incomplete understanding of the role of IDO1 and the consequent degradation of tryptophan in mRNA translation and cancer progression. Here we used ribosome profiling in melanoma cells to investigate the effects of prolonged IFNγ treatment on mRNA translation. Notably, we observed accumulations of ribosomes downstream of tryptophan codons, along with their expected stalling at the tryptophan codon. This suggested that ribosomes bypass tryptophan codons in the absence of tryptophan. A detailed examination of these tryptophan-associated accumulations of ribosomes—which we term ‘W-bumps’—showed that they were characterized by ribosomal frameshifting events. Consistently, reporter assays combined with proteomic and immunopeptidomic analyses demonstrated the induction of ribosomal frameshifting, and the generation and presentation of aberrant trans-frame peptides at the cell surface after treatment with IFNγ. Priming of naive T cells from healthy donors with aberrant peptides induced peptide-specific T cells. Together, our results suggest that IDO1-mediated depletion of tryptophan, which is induced by IFNγ, has a role in the immune recognition of melanoma cells by contributing to diversification of the peptidome landscape.

Date: 2021
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DOI: 10.1038/s41586-020-03054-1

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