Anti-tumour immunity induces aberrant peptide presentation in melanoma
Bartok, Osnat; Pataskar, Abhijeet; Nagel, Remco; Laos, Maarja; Goldfarb, Eden; Hayoun, Deborah; Levy, Ronen; Körner, Pierre-Rene; Kreuger, Inger Z M; Champagne, Julien; Zaal, Esther A; Bleijerveld, Onno B; Huang, Xinyao; Kenski, Juliana; Wargo, Jennifer; Brandis, Alexander; Levin, Yishai; Mizrahi, Orel; Alon, Michal; Lebon, Sacha; Yang, Weiwen; Nielsen, Morten M; Stern-Ginossar, Noam; Altelaar, Maarten; Berkers, Celia R; Geiger, Tamar; Peeper, Daniel S; Olweus, Johanna; Samuels, Yardena; Agami, Reuven
(2021) Nature, volume 590, issue 7845, pp.
(Article)
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
... read more
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.
show less
Download/Full Text
Keywords: Taverne, General
ISSN: 0028-0836
Publisher: Nature Research
Note: Funding Information: Acknowledgements R.A. is supported by the Dutch Cancer Society (KWF projects 10315, 11037 and 11574), the European Research Council (ERC–PoC 665317 and ERC-AdG 832844) and the Dutch science organization (NWO-TOP 91216002).Y.S. is supported by the Israel Science Foundation grant no. 696/17, the ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 770854), MRA (622106), Israel Science Foundation (696/17), Rising Tide Foundation, Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, Estate of Alice Schwarz-Gardos, Estate of John Hunter, Knell Family and the Hamburger Family. A.P. is supported by a long-term EMBO fellowship grant (EMBO ALTF 796-2018). O.B.B. and M. Alterlaar are supported by the Dutch NWO X-omics Initiative. J.O. and M.L. are supported by the South-Eastern Regional Health Authority Norway, the Research Council of Norway, the Norwegian Cancer Society, Stiftelsen Kristian Gerhard Jebsen, the University of Oslo and Oslo University Hospital. We thank M. Delic-Sarac, S. Meyer and T. J. Gjerdingen for HLA typing and processing of blood from in-house healthy donors; P. Kvistborg for providing selected tetramers; and S. Reich-Zeliger, A. Nachshon, L. Eisenbach, A. Navon, S. Pinto, A. Peri, S. Cohen, A. Admon, A. Kacen and all members of the Agami laboratory for discussions. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
(Peer reviewed)