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Analysis of the T cell’s Tactical Arsenal for Cancer Killing

Objective

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.

Call for proposal

ERC-2020-SyG
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Host institution

UNIVERSITAT DES SAARLANDES
Address
Campus
66123 Saarbrucken
Germany
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 742 037

Beneficiaries (4)

UNIVERSITAT DES SAARLANDES
Germany
EU contribution
€ 2 742 037
Address
Campus
66123 Saarbrucken
Activity type
Higher or Secondary Education Establishments
UNIVERSITA DEGLI STUDI DI SIENA
Italy
EU contribution
€ 2 339 947
Address
Via Banchi Di Sotto 55
53100 Siena
Activity type
Higher or Secondary Education Establishments
THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom
EU contribution
€ 2 454 543
Address
Wellington Square University Offices
OX1 2JD Oxford
Activity type
Higher or Secondary Education Establishments
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France
EU contribution
€ 2 462 490
Address
Rue De Tolbiac 101
75654 Paris
Activity type
Research Organisations