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 - 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.
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 -
