Translational control of tumor immune escape via the eIF4F–STAT1–PD-L1 axis in melanoma
(2018) In Nature Medicine 24(12). p.1877-1886- 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.... (More)
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.
(Less)
- author
- publishing date
- 2018-12-01
- type
- Contribution to journal
- publication status
- published
- in
- Nature Medicine
- volume
- 24
- issue
- 12
- pages
- 1877 - 1886
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:30374200
- scopus:85055719664
- ISSN
- 1078-8956
- DOI
- 10.1038/s41591-018-0217-1
- language
- English
- LU publication?
- no
- additional info
- 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.
- id
- 28d3e987-c10b-4110-b09a-fe9e0db0905f
- date added to LUP
- 2022-03-28 14:50:41
- date last changed
- 2024-06-19 02:55:59
@article{28d3e987-c10b-4110-b09a-fe9e0db0905f,
abstract = {{<p>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.</p>}},
author = {{Cerezo, Michaël and Guemiri, Ramdane and Druillennec, Sabine and Girault, Isabelle and Malka-Mahieu, Hélène and Shen, Shensi and Allard, Delphine and Martineau, Sylvain and Welsch, Caroline and Agoussi, Sandrine and Estrada, Charlène and Adam, Julien and Libenciuc, Cristina and Routier, Emilie and Roy, Séverine and Désaubry, Laurent and Eggermont, Alexander M. and Sonenberg, Nahum and Scoazec, Jean Yves and Eychène, Alain and Vagner, Stéphan and Robert, Caroline}},
issn = {{1078-8956}},
language = {{eng}},
month = {{12}},
number = {{12}},
pages = {{1877--1886}},
publisher = {{Nature Publishing Group}},
series = {{Nature Medicine}},
title = {{Translational control of tumor immune escape via the eIF4F–STAT1–PD-L1 axis in melanoma}},
url = {{http://dx.doi.org/10.1038/s41591-018-0217-1}},
doi = {{10.1038/s41591-018-0217-1}},
volume = {{24}},
year = {{2018}},
}