TY - JOUR
T1 - Anti-tumour immunity induces aberrant peptide presentation in melanoma
AU - Bartok, Osnat
AU - Pataskar, Abhijeet
AU - Nagel, Remco
AU - Laos, Maarja
AU - Goldfarb, Eden
AU - Hayoun, Deborah
AU - Levy, Ronen
AU - Körner, Pierre-Rene
AU - Kreuger, Inger Z M
AU - Champagne, Julien
AU - Zaal, Esther A
AU - Bleijerveld, Onno B
AU - Huang, Xinyao
AU - Kenski, Juliana
AU - Wargo, Jennifer
AU - Brandis, Alexander
AU - Levin, Yishai
AU - Mizrahi, Orel
AU - Alon, Michal
AU - Lebon, Sacha
AU - Yang, Weiwen
AU - Nielsen, Morten M
AU - Stern-Ginossar, Noam
AU - Altelaar, Maarten
AU - Berkers, Celia R
AU - Geiger, Tamar
AU - Peeper, Daniel S
AU - Olweus, Johanna
AU - Samuels, Yardena
AU - Agami, Reuven
N1 - Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/2/11
Y1 - 2021/2/11
N2 - 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 immunotherapy. 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 IFNγ. 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 alone, 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.
AB - 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 immunotherapy. 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 IFNγ. 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 alone, 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.
UR - http://www.scopus.com/inward/record.url?scp=85097607652&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41586-020-03054-1
DO - https://doi.org/10.1038/s41586-020-03054-1
M3 - مقالة
C2 - 33328638
SN - 0028-0836
VL - 590
SP - 332
EP - 337
JO - Nature
JF - Nature
IS - 7845
ER -