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Translational control of tumor immune escape via the eIF4F–STAT1–PD-L1 axis in melanoma

Abstract

Preventing the immune escape of tumor cells by blocking inhibitory checkpoints, such as the interaction between programmed death ligand-1 (PD-L1) and programmed death-1 (PD-1) receptor, is a powerful anticancer approach. However, many patients do not respond to checkpoint blockade. Tumor PD-L1 expression is a potential efficacy biomarker, but the complex mechanisms underlying its regulation are not completely understood. Here, we show that the eukaryotic translation initiation complex, eIF4F, which binds the 5′ cap of mRNAs, regulates the surface expression of interferon-γ-induced PD-L1 on cancer cells by regulating translation of the mRNA encoding the signal transducer and activator of transcription 1 (STAT1) transcription factor. eIF4F complex formation correlates with response to immunotherapy in human melanoma. Pharmacological inhibition of eIF4A, the RNA helicase component of eIF4F, elicits powerful antitumor immune-mediated effects via PD-L1 downregulation. Thus, eIF4A inhibitors, in development as anticancer drugs, may also act as cancer immunotherapies.

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Fig. 1: eIF4F inhibition blocks PD-L1 induction in cancer cells.
Fig. 2: eIF4F stimulation increases PD-L1 induction in melanoma cells.
Fig. 3: eIF4F complex formation is correlated with inducible PD-L1 expression in melanoma patient samples.
Fig. 4: eIF4F regulates the translation of the STAT1 mRNA.
Fig. 5: eIF4F-dependent regulation of STAT1 is a key mediator of inducible PD-L1.
Fig. 6: Targeting eIF4F inhibits tumor growth via PD-L1 and the immune system.

Data availability

The data sets generated for this study can be accessed at GEO (GSE118521). Uncropped immunoblots are available in Supplementary Fig. 13, data obtained from human tumor samples in Supplementary Table 4 and primer sequences in Supplementary Table 5.

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Acknowledgements

We thank M. A. Shipp for the PD-L1 luciferase promoter, J. Wargo for the BRAF/PTEN mouse cell line (BP), S. Rocchi for the CMVβGal plasmid and WM793 melanoma cells and M.-P. Teulade-Fichou for the PhenDC3. We thank the Institut Curie Genomics (A. Rapinat and D. Gentien) platform for assistance with the microarray experiments and the animal facility of the Orsay site of the Institut Curie. We thank the Gustave Roussy platform ‘Module de developpement en pathologie INSERM U981/SIRI SOCRATE’ and ‘Plateforme d’évaluation Préclinique’. We thank M. Tichet, M. Khaled and S. Apcher for helpful discussions. This study was supported by INSERM, CNRS, Gustave Roussy and Institut Curie. This study was also funded by grants from Ligue Nationale Contre le Cancer (Equipe labellisée) (to S.V. and A.E.), Institut National du Cancer (grant number 2013-1-MEL-01-ICR-1) (to S.V., A.E. and C.R.), ‘Ensemble contre le mélanome’ (to C.R. and S.V.), ‘Vaincre le Mélanome’ (to M.C. and C.R.), Les Sites de recherche Intégré sur le Cancer (SIRIC Socrate) label Gustave Roussy (to C.R.), Fondation Bettencourt Schueller (to C.R.) and Fondation ARC pour la Recherche sur le Cancer (project PJA20161204588) (to S.S.). M.C. was supported by a post-doctoral fellowship from ‘Association pour la recherche contre le cancer’ and R.G. was supported by a pre-doctoral fellowship from ‘Fondation pour la Recherche Médicale, (FDT2017043739).

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Contributions

M.C. and R.G. designed and performed in vitro and in vivo experiments and analyzed data. H.M.-M. established the silvestrol-resistant cell line, the BrafV600E4ebp1−/−4ebp2−/− cell lines and performed associated experiments. S.D., C.E. and A.E. established the BrafV600E4ebp1−/−4ebp2−/− mouse model and BrafV600E4ebp1−/−4ebp2−/− cell lines and analyzed data. S.S. contributed to microarray data analysis. D.A. contributed to in vivo experiments. I.G., C.W. and S.A. performed experiments on patient samples and analyzed data. S.M. performed polysomal fractionation. J.A. and J.Y.S. analyzed IHC and PLA on human samples. C.L., E.R. and S.R. provided clinical samples. L.D. provided FL3. N.S., A.M.E. and A.E. gave advice; M.C., S.V. and C.R. wrote the manuscript. M.C. and R.G. share first authorship; S.D., I.G. and H.M.-M. share second authorship; S.V. and C.R. supervised all research and are joint senior authors.

Corresponding authors

Correspondence to Stéphan Vagner or Caroline Robert.

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Competing interests

C.R. is an occasional consultant to Merck Sharp and Dohme, Bristol-Myers Squibb, Merck and Roche. All other authors have no competing interests.

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Supplementary Information

Supplementary Text and Figures

Supplementary Figures 1–13 and Supplementary Table 3

Reporting Summary

Supplementary Table 1

Change in mRNA in IFN-γ-treated cells compared to untreated

Supplementary Table 2

mRNA downregulated translationally by silvestrol and upregulated transcriptionally by IFN-γ

Supplementary Table 4

Data from human tumor samples

Supplementary Table 5

Primer sequences

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Cerezo, M., Guemiri, R., Druillennec, S. et al. Translational control of tumor immune escape via the eIF4F–STAT1–PD-L1 axis in melanoma. Nat Med 24, 1877–1886 (2018). https://doi.org/10.1038/s41591-018-0217-1

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