Press releases

A new pathway for modulating anti-tumoral immune response

14 Nov 2018 | By INSERM (Newsroom) | Cancer

Cellules cancéreuses d’un mélanome.  Inserm/Valencia, Julio C., 2018

Researchers from Inserm, CNRS, Paris-Sud University, Gustave Roussy, and Institut Curie have identified a new agent in regulating PD-L1 gene expression: the eIF4F complex, which plays a role in controlling protein synthesis.

This complex could become a predictive marker for response to immunotherapy. Furthermore, the researchers demonstrate, for the first time, that inhibition of the eIF4F complex gives rise to an anti-tumoral effect related to decreased PD-L1 expression, which therefore elicits immune system intervention.

The researchers hope that eIF4F inhibitors will be able to be used as anti-cancer agents in the future, alone or, more than likely, in combination with other treatments.

Just a few years ago, the immune system, our defense against disease, seemed unequipped to fight cancer. Advances in immunotherapy are making it possible to correct these shortcomings: the immune system can now learn to recognize and destroy cancer cells. Lymphocytes are thus rediscovering their initial ability to fight rather than protect tumors.

The PD-1 (programmed cell death) molecule, expressed on the surface of T cells, binds to another molecule present on the surface of certain tumor or immune cells, PD-L1. This interaction in a way renders the tumor cell invisible to the immune system, by deactivating (or disarming) T cells.

In recent years, immunotherapy targeting the PD-L1/PD-1 interaction has revolutionized the treatment of melanoma and other types of cancer.

However, many patients do not respond to treatment. These agents are highly effective for several months or years, but only in 10 to 20% of patients, for all types of cancer combined.

The development of biomarkers is therefore a key issue in identifying patients liable to respond to treatment,” explains Professor Caroline Robert, Head of the Dermatology Department at Gustave Roussy.

A high PD-L1 level in tumors is a major indicator since this is often associated with a good response to anti-PD1 agents. However, the mechanisms for regulating PD-L1 expression have not been fully elucidated,” points out Stephan Vagner, Inserm Research Director and Head of the RNA Biology Team at Institut Curie.

In this latest publication, the researchers demonstrate, for the first time, that a complex known as eIF4F, involved in initiating the translation of messenger RNA into proteins, regulates PD-L1 expression and that, by targeting eIF4F in tumor cells, anti-tumoral immunity can be stimulated, thus mimicking the effect of immunotherapy.

In this study, the researchers mainly used melanoma as a model, but also conducted tests with lung cancer, breast cancer, and colon cancer cells.

They will now go on to evaluate the findings of the study on the formation of the eIF4F complex, as a predictive marker for response to immunotherapy.

They are, moreover, developing other melanoma treatment models, based on the use of eIF4F complex inhibitors, in combination with other treatments, to increase therapeutic efficacy and fight resistance.

This study was supported by Inserm, CNRS, Gustave Roussy, and Institut Curie. It was also funded by the Ligue Nationale Contre le Cancer (accredited team), French National Cancer Institute, the ‘Ensemble contre le mélanome’ collective, and the ‘Vaincre le Mélanome’ association, SIRIC Socrate, Fondation Bettencourt Schueller, and Fondation ARC for Cancer Research.
Researcher Contact
Stephan Vagner Chercheur Inserm Responsable de l'équipe Biologie de l'ARN en réponse aux dommages de l'ADN Unité Mixte de recherche 3348 Stress génotoxique et cancer 01 69 86 31 03 rf.eiruc@rengav.nahpets Caroline Robert Unité Inserm 981 Identifiction de nouvelles cibles thérapeutiques en cancérologie 01 42 11 42 10 rf.yssuorevatsug@trebor.enilorac
Press Contact
Gustave Roussy : Claire Parisel 01 42 11 50 59 rf.yssuorevatsug@lesirap.erialc Institut Curie : Catherine Goupillon 01 56 24 55 23 rf.eiruc@esserp.ecivres Inserm rf.mresni@esserp
'Translational control of tumor immune escape via the eIF4F–STAT1–PD-L1 axis in melanoma' Nature Medicine DOI 10.1038/s41591-018-0217-1. 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