UNPACK PD-L1 · Molecular mechanism and inhibition of extracellular vesicle-mediated PD-L1 release in melanoma cells
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-02-01 → 2022-01-31
- EU contribution
- €175,572
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Molecular mechanism and inhibition of extracellular vesicle-mediated PD-L1 release in melanoma cells
Millions of tiny packages released from cells, full of ‘molecular mail’ are racing through your bloodstream right now, and they allow the cells of your body to work in harmony. However, when these packages (that we call exosomes), originate from cancer cells, they flood the body to promote a ‘pro-tumorigenic’ environment - helping the cancer survive, spread and resist effective therapy. I want to unravel the molecular machinery that cancer cells use to create these packages and send their manipulative messages, in order to learn how to stop this method of cancer communication, and slow disease progression. One of those manipulative messages they carry (called programmed-death ligand 1 or simply "PD-L1"), inactivates immune cell function that would otherwise recognize and kill the tumor. My project aimed to understand the molecular mechanism of how cancer cells can send out this particular immune-dampening message into circulation, and search for drugs that may be able to stop this process. The ultimate goal would be to develop new therapies that remove this blockade, restore the immune detection of the cancer, and thus limit the spread and progression of the disease.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- STICHTING AMSTERDAM UMC · AmsterdamCoordinatorNetherlands
Links
- View on CORDIS
- DOI: 10.3030/845391
- http://www.exosomes.nl/marie-sk322odowska-curie-postdoctoral-fellow.html
Data: CORDIS, © European Union