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.
Michaël Cerezo 1,2,12, Ramdane Guemiri1,2,3,4,5,12, Sabine Druillennec5,6,7, Isabelle Girault1,2, Hélène Malka-Mahieu3,4,5, Shensi Shen 1,2, Delphine Allard1,2, Sylvain Martineau3,4,5, Caroline Welsch1,2,3,4,5, Sandrine Agoussi1,2, Charlène Estrada5,6,7, Julien Adam1,8, Cristina Libenciuc9, Emilie Routier9, Séverine Roy9, Laurent Désaubry10, Alexander M. Eggermont2,9, Nahum Sonenberg11, Jean Yves Scoazec 8, Alain Eychène 5,6,7, Stéphan Vagner 3,4,5,9,13* and Caroline Robert1,2,9,13*
1INSERM U981, Gustave Roussy, Villejuif, France
2Université Paris-Sud, Université Paris-Saclay, Kremlin-Bicêtre, France
3Institut Curie, PSL Research University, CNRS UMR 3348, Orsay, France
4Université Paris-Sud, Université Paris-Saclay, CNRS UMR 3348, Orsay, France
5Equipe Labellisée Ligue Contre le Cancer, Paris, France
6Institut Curie, PSL Research University, CNRS UMR 3347, INSERM U1021, Orsay, France
7Université Paris-Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France
8Department of Pathology and Laboratory Medicine (BIOpath), Gustave Roussy, Univesité Paris-Saclay, Villejuif, France
9Oncology Department, Gustave Roussy, Université Paris-Saclay, Villejuif, France
10CNRS-Strasbourg University, UMR7200, Illkirch, France
11Department of Biochemistry, McGill University, Montréal, Québec, Canada
12These authors contributed equally: Michaël Cerezo, Ramdane Guemiri.
13These authors jointly supervised this work: Stéphan Vagner, Caroline Robert