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Molecular mechanism and inhibition of extracellular vesicle-mediated PD-L1 release in melanoma cells

Project description

Chasing down extracellular vesicles carrying carcinogenic molecules

Targeted drug therapies for numerous diseases and conditions focus on cell membrane-bound receptors or intracellular molecules including nuclear ones. However, the story appears more complicated. A small transmembrane molecule called PD-L1 helps tumour cells evade a body's anti-tumour immune response. Recently, research has shown that it also gets packaged in extracellular vesicles and released from the cell, after which its distribution is systemic. UNPACK PD-L1 plans to elucidate the mechanisms of this process, as it seems to affect patients’ response to certain tumour immunosuppression therapies. Better understanding should help develop inhibitors of extracellular release to restore immunosuppression of tumour growth.


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.


Net EU contribution
€ 175 572,48
1081 HV Amsterdam

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West-Nederland Noord-Holland Groot-Amsterdam
Activity type
Research Organisations
Total cost
€ 175 572,48