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

Michaël Cerezo, Ramdane Guemiri, Sabine Druillennec, Isabelle Girault, Hélène Malka-Mahieu, Shensi Shen, Delphine Allard, Sylvain Martineau, Caroline Welsch, Sandrine Agoussi, Charlène Estrada, Julien Adam, Cristina Libenciuc, Emilie Routier, Séverine Roy, Laurent Désaubry, Alexander M. Eggermont, Nahum Sonenberg, Jean Yves Scoazec, Alain EychèneStéphan Vagner, Caroline Robert

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

165 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)1877-1886
Aantal pagina's10
TijdschriftNature Medicine
Volume24
Nummer van het tijdschrift12
DOI's
StatusGepubliceerd - 1 dec. 2018
Extern gepubliceerdJa

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