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 LebonWeiwen Yang, Morten M. Nielsen, Noam Stern-Ginossar, Maarten Altelaar, Celia R. Berkers, Tamar Geiger, Daniel S. Peeper, Johanna Olweus, Yardena Samuels*, Reuven Agami*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)332-337
Number of pages6
JournalNature
Volume590
Issue number7845
DOIs
StatePublished - 11 Feb 2021

Funding

FundersFunder number
Dutch Cancer Society
Dutch Science Organization
NWO-TOP91216002
South-Eastern Regional Health Authority Norway
Kreftforeningen
Horizon 2020 Framework Programme832844, 770854
European Research Council665317
Oslo University College
Israel Science Foundation696/17
KWF Kankerbestrijding10315, 11574, 11037
Norges Forskningsråd
Ministry of Rural Affairs622106
Rising Tide FoundationEMBO ALTF 796-2018

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