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

Project Information

UNPACK PD-L1

Grant agreement ID: 845391

DOI

10.3030/845391

Project closed

EC signature date 9 April 2019

Start date 1 February 2020

End date 31 January 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 175 572,48

EU contribution

€ 175 572,48

Coordinated by

STICHTING AMSTERDAM UMC
Netherlands

Periodic Reporting for period 1 - UNPACK PD-L1 (Molecular mechanism and inhibition of extracellular vesicle-mediated PD-L1 release in melanoma cells)

Reporting period: 2020-02-01 to 2022-01-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Herein, I have sought 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 knowledge was then exploited to screen a large library of drugs, in search for for candidates that can inhibit PD-L1 release and restore immune cell function.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Ideally the outcome of this in vitro study will provide a strong rationale for combining anti-PD-1 agents with inhibitors of PD-L1 secretion, to be tested in pre-clinical mouse models. If successful, EV blockade may remove the unanticipated bottlenecks that surround the efficacy of current immune modulatory drugs (anti-PD-1 therapy). In the long term this study is meant to lay groundwork for inhibiting the many pro-tumorigenic messages carried by this particular communication channel (exosomes) inhibition as a therapeutic strategy for many human cancer types, and open up new and better therapies for patients.

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