Project description DEENESFRITPL Cytotoxic T cell proteins in the fight against cancer Cytotoxic T lymphocytes (CTLs) release cytotoxic protein complexes, known as supramolecular attack particles (SMAPs), that kill infected and cancer cells. SMAPs consist of an outer core structure and assemble in the secretory granules of CTLs. The EU-funded ATTACK project will bring together leaders in the field of immunology to dissect the precise mechanism by which SMAPs are generated, their mode of action and the process by which they kill cancer cells. The idea is to exploit this information for isolating natural or producing synthetic SMAPs independent of CTLs as an anticancer strategy. The proposed approach can be employed alone or in combination with engineered T cells. Show the project objective Hide the project objective 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. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineimmunologymedical and health sciencesclinical medicineoncology Keywords immunological synapse cytotoxic T lymphocytes cytotoxic granule biogenesis trafficking and fusion Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2020-SyG - ERC Synergy Grant Call for proposal ERC-2020-SyG See other projects for this call Funding Scheme ERC-SyG - Synergy grant Coordinator THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD Net EU contribution € 2 537 877,00 Address Wellington square university offices OX1 2JD Oxford United Kingdom See on map Region South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,50 Beneficiaries (4) Sort alphabetically Sort by Net EU contribution Expand all Collapse all THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD United Kingdom Net EU contribution € 2 537 877,00 Address Wellington square university offices OX1 2JD Oxford See on map Region South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,50 UNIVERSITA DEGLI STUDI DI SIENA Italy Net EU contribution € 2 423 281,00 Address Via banchi di sotto 55 53100 Siena See on map Region Centro (IT) Toscana Siena Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,25 UNIVERSITAT DES SAARLANDES Germany Net EU contribution € 2 492 037,00 Address Campus 66123 Saarbrucken See on map Region Saarland Saarland Regionalverband Saarbrücken Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,50 INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE France Net EU contribution € 2 545 822,00 Address Rue de tolbiac 101 75654 Paris See on map Region Ile-de-France Ile-de-France Paris Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,75
