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

Información del proyecto

UNPACK PD-L1

Identificador del acuerdo de subvención: 845391

DOI

10.3030/845391

Proyecto cerrado

Fecha de la firma de la CE 9 Abril 2019

Fecha de inicio 1 Febrero 2020

Fecha de finalización 31 Enero 2022

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 175 572,48

Aportación de la UE

€ 175 572,48

Coordinado por

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)

Período documentado: 2020-02-01 hasta 2022-01-31

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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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