Projektbeschreibung
Proteine aus zytotoxischen T-Zellen für die Krebstherapie
Zytotoxische T-Lymphozyten (CTL) produzieren zytotoxische Proteinkomplexe bzw. supramolekulare Angriffspartikel (SMAP), die infizierte Zellen und Krebszellen eliminieren. Supramolekulare Angriffspartikel bestehen aus einer äußeren Kernstruktur und bilden sich in den sekretorischen Granula zytotoxischer T-Lymphozyten. Im EU-finanzierten Projekt ATTACK analysieren Spitzenforschende aus dem Bereich Immunologie im Detail die Erzeugung von SMAP sowie deren Wirkungsweise und Eliminierung von Krebszellen. Auf dieser Basis sollen dann natürliche SMAP isoliert oder SMAP synthetisch und unabhängig von zytotoxischen T-Lymphozyten erzeugt werden, um daraus Krebsmedikamente zu entwickeln. Der vorgeschlagene Ansatz kann allein oder in Kombination mit biotechnologischen T-Zellen zum Einsatz kommen.
Ziel
The ATTACK consortium will develop a new biotechnology based on harnessing a previously unknown natural cytotoxic mechanism of T cells to fight cancer. Cytotoxic T cells (CTL) protect us against intracellular pathogens and cancer by killing infected and cancerous cells. It has been believed that CTL operate on two different time scales of killing by releasing soluble cytotoxic proteins from dense core granules into the immunological synapse between the T cell and target cells (seconds/minutes) and by FasL-mediated apoptosis (hours/days). Members of the ATTACK consortium have independent observations that converge on a previously unknown weapon in the T cell tactical arsenal: stable supramolecular attack particles (SMAPs) that kill target cells (hours). This raises the possibility to engineer these particles to operate independent of T cells. Baldari has discovered that intraflagellar transport proteins sort cytotoxic proteins within the CTL. Rettig has revealed a new storage depot in CTL called a multicore granule that is distinct from the dense core granule. Dustin uncovered that CTL release SMAPs into the immunological synapse to kill targets. Valitutti has called attention to active resistance of tumour cells to synaptic attack, highlighting the strategic advantage of a non-synaptic attack. The consortium has expertise in mouse models, gene editing in primary T cells, super-resolution and live cell microscopy, and microfluidics. The goal of the ATTACK consortium will be to work closely together through 4 work-packages to determine 1) how SMAPs are made, 2) how they are released, 3) how they work and 4) how cancer cells respond. The consortium will integrate all it learns to develop the biotechnology of SMAP enhancement in engineered T cells, recombinant SMAPs, and synthetic SMAPs. We envision that SMAPs will be freeze-dried and shipped around the world, solving problems related to current immunotherapies, leading to global health impact.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
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Finanzierungsplan
ERC-SyG - Synergy grantGastgebende Einrichtung
OX1 2JD Oxford
Vereinigtes Königreich