Descrizione del progetto
Inseguire le vescicole extracellulari che trasportano molecole cancerogene
Le terapie farmacologiche mirate per numerose malattie e condizioni si focalizzano su recettori legati alla membrana cellulare o su molecole intracellulari, comprese quelle nucleari. La storia sembra tuttavia più complicata. Una piccola molecola transmembrana, denominata PD-L1, aiuta le cellule tumorali a eludere la risposta immunitaria antitumorale di un organismo. Recentemente, la ricerca ha dimostrato che questa molecola viene anche impacchettata in vescicole extracellulari e quindi rilasciata dalla cellula, dopo di che la sua distribuzione diventa sistemica. UNPACK PD-L1 intende chiarire i meccanismi di questo processo, poiché sembra influenzare la risposta dei pazienti a determinate terapie di immunosoppressione tumorale. Una migliore comprensione dovrebbe aiutare a sviluppare inibitori del rilascio extracellulare per ripristinare l’immunosoppressione della crescita tumorale.
Obiettivo
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.
Campo scientifico
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Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
1081 HV Amsterdam
Paesi Bassi