Description du projet
Traquer les vésicules extracellulaires porteuses de molécules cancérogènes
Les traitements médicamenteux ciblés pour différentes maladies et affections ciblent les récepteurs liés à la membrane cellulaire ou les molécules intracellulaires, y compris les nucléaires. La réalité semble toutefois plus complexe. Une petite molécule transmembranaire appelée PD-L1 aide les cellules tumorales à déjouer une immunoréaction antitumorale du corps. Récemment, des recherches ont montré qu’elle se trouve également prise dans des vésicules extracellulaires et est libérée par la cellule, sa distribution devient donc systémique. UNPACK PD-L1 prévoit d’examiner les mécanismes de ce processus, étant donné qu’il semble affecter la réaction des patients à certaines thérapies d’immunosuppression tumorale. Une meilleure compréhension devrait aider à développer des inhibiteurs de libération extracellulaire, afin de restaurer l’immunosuppression de la croissance tumorale.
Objectif
Harnessing the power of the immune system to treat cancer has long been a sought after goal of oncological research. Immune checkpoint inhibitors, such as anti-programmed death receptor 1 (PD-1) blockade therapies, have now taken center stage. However not all patients respond, highlighting gaps in our understanding of the mechanisms of tumour immunosuppression. Upregulation of the PD-1 ligand (PD-L1) on tumour cells initiated this therapeutic direction, yet it is becoming clear that the modality of PD-L1-mediated immune suppression is not limited to the plasma membrane. Like many tumor cells, melanoma cells secrete small extracellular vesicles (EVs) with pro-tumorigenic properties. Melanoma EVs express PD-L1 that suppress T cell function and facilitate tumour growth in pre-clinical mouse models. This systemic mechanism is clinically relevant, as circulating EV-PD-L1 levels can stratify anti-PD-1 clinical responders from non-responders. Thus inhibiting EV-PD-L1 may increase anti-PD-1 efficacy and broaden the responder bracket. One plausible strategy would be to block tumor EV secretion, yet little is known about the molecular mechanisms that drive PD-L1 loading and release. Herein, I intend to uncover the molecular mechanisms of EV PD-L1 release from melanoma cells using state-of-the-art optical and bioluminescent reporters to reveal novel druggable targets. This basic knowledge will be exploited to guide subsequent inhibition, through a drug screen for candidates that inhibit EV-PD-L1 release and restore T cell function. Ideally the outcome of this in vitro study will provide a strong rationale for combining anti-PD-1 agents with inhibitors of EV-PD-L1 secretion, to be tested in pre-clinical mouse models. If successful, melanoma EV blockade may remove the unanticipated bottlenecks that surround the efficacy of anti-PD-1 therapy. In the long term this study is meant to lay groundwork for tumor EV inhibition as a therapeutic strategy for cancer types beyond melanoma.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF-EF-ST - Standard EFCoordinateur
1081 HV Amsterdam
Pays-Bas