Descripción del proyecto
Localización de las vesículas extracelulares que contienen moléculas carcinogénicas
Las terapias dirigidas de fármacos para numerosas enfermedades y afecciones se centran en los receptores unidos a membranas celulares o moléculas intracelulares, incluidas las nucleares. Sin embargo, este proceso resulta más complicado. Una pequeña molécula transmembrana llamada PD-L1 ayuda a las células tumorales a eludir la respuesta inmunitaria antitumoral del cuerpo. Hace poco, las investigaciones han demostrado que también se empaqueta en vesículas extracelulares y se secreta de la célula, después de lo cual su distribución es sistémica. UNPACK PD-L1 prevé elucidar los mecanismos de este proceso, ya que parece que afecta a la respuesta de los pacientes a los tratamientos de inmunosupresión tumoral. Una mejor comprensión debería ayudar a desarrollar inhibidores de secreción extracelular para restaurar la inmunosupresión del crecimiento tumoral.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF-EF-ST - Standard EFCoordinador
1081 HV Amsterdam
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