TY - JOUR
T1 - Translational control of tumor immune escape via the eIF4F–STAT1–PD-L1 axis in melanoma
AU - Cerezo, Michaël
AU - Guemiri, Ramdane
AU - Druillennec, Sabine
AU - Girault, Isabelle
AU - Malka-Mahieu, Hélène
AU - Shen, Shensi
AU - Allard, Delphine
AU - Martineau, Sylvain
AU - Welsch, Caroline
AU - Agoussi, Sandrine
AU - Estrada, Charlène
AU - Adam, Julien
AU - Libenciuc, Cristina
AU - Routier, Emilie
AU - Roy, Séverine
AU - Désaubry, Laurent
AU - Eggermont, Alexander M.
AU - Sonenberg, Nahum
AU - Scoazec, Jean Yves
AU - Eychène, Alain
AU - Vagner, Stéphan
AU - Robert, Caroline
N1 - Funding Information:
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).
Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055719664&partnerID=8YFLogxK
U2 - 10.1038/s41591-018-0217-1
DO - 10.1038/s41591-018-0217-1
M3 - Article
C2 - 30374200
AN - SCOPUS:85055719664
SN - 1078-8956
VL - 24
SP - 1877
EP - 1886
JO - Nature Medicine
JF - Nature Medicine
IS - 12
ER -
