Project description
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.
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 (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. This project's classification has been validated by the project's team.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. This project's classification has been validated by the project's team.
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Funding Scheme
ERC-SyG - Synergy grantHost institution
OX1 2JD Oxford
United Kingdom