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

Informations projet

ATTACK

N° de convention de subvention: 951329

DOI

10.3030/951329

Date de signature de la CE 25 Avril 2021

Date de début 1 Mai 2021

Date de fin 30 Avril 2027

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 9 999 019,00

Contribution de l’UE

€ 9 999 017,00

Coordonné par

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom

Periodic Reporting for period 3 - ATTACK (Analysis of the T cell’s Tactical Arsenal for Cancer Killing)

Période du rapport: 2024-05-01 au 2025-10-31

Résumé du contexte et des objectifs généraux du projet

Nearly 10 million people die of cancer worldwide every year. It is therefore of great importance to research the body's own defense strategies against cancer cells in order to enable new therapies. Two groups of white blood cells, killer T cells and natural killer cells, play an important role in the fight against tumor cells using an arsenal of molecular toxins. All cells display information on the surface that act like identification badges and discrepancies in this information, or failure to display any identification, can induce the killer white blood cells to attack. The killer cell’s arsenal includes releasing a cocktail of toxins in points of physical contact between the killer white blood cells and the tumour cells, the immunological synapse.

The toxins open holes in the tumour cells and induce a self-destruction sequence. The toxins can be released in a spray-like form or in bomb shell-like supramolecular attack particles (SMAPs), in which a sugary shell encapsulates the toxic core. SMAPs are tumour killing entities and biotechnology based on SMAPs would be a completely new approach not only in cancer therapy, but also as a treatment for chronic infection and potentially in regenerative medicine through delivery of non-toxic cargo for tissue repair.

Since May 2021, an international team of researchers in Siena, Homburg, Oxford and Toulouse has worked together as a superlab to pursue precisely this goal within an ERC Synergy Programme titled Analysis of the T cells Tactical Arsenal for Cancer Killing or ATTACK. ATTACK is investigating how SMAPs are made (Siena), how they are released (Homburg), how they work (Oxford) and how cancer cells respond (Toulouse). The overall objective is to understand this new molecularly defined tumour killing system so as to address current limitations of cancer and chronic viral infection immunotherapy and have a transformative global health impact.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

a) We maintain a web site (https://supramolecular-attack-particles.eu) to communicate discoveries to the public.

b) We have collaborated on publications explaining the functional role of SMAPs in the context of the CTL lytic arsenal to the scientific community, published methods to enable the work of other scientists in this area and have published original research on SMAPs (PMID:37325629; 35514977; 35592329; 37106198; 37106201; 34446922; 33782566; 36593148). Others have positively reviewed work from ATTACK (e.g. PMID:36737375; 35927511).

c) We identified the storage sites for the spray-like and bomb-like release of cells destroying molecules. These storage sites are referred to as “granules” and differ in diameter, shape and composition, but also in the type with which their cytotoxic contents are released (PMID:35210420).

d) Cancer cells respond to killer T cell attack within seconds and create a defensive line that protects the core of solid tumors, a challenge facing immunotherapy approaches (PMID:35171665).

e) Initiated during the Covid-19 pandemic, we contributed to our fundamental understanding of SARS-Cov2 mediated immune evasion by demonstrating that the spike protein inhibits immunological synapse formation (PMID:36378226).

f) ATTACK has published initial guidelines on how to identify SMAPs in images and how to prepare SMAPs from human T cells, setting the stage for diagnostics and large-scale manufacturing. This was published as part of the release of our patent-pending computational strategy for image analysis pipelines that are fully explainable (PMID:37932311; International patent application PCT/EP2024/053346).

g) We gained new insights into the interplay of two components in SMAP's "bomb-shell", SMAP-mediated killing and cancer cell defense tactic through suppression of bomb-shell protein expression in immune cells (PMID:39903110).

h) We have shared findings on a novel granzyme-independent target cell pyroptotic cell death pathway triggered by perforin-mediated pore formation at the lytic synapse (doi.org/10.1101/2024.05.24.595698).

i) We have shared findings on a new T cell killing mechanism based on lytic IFN that is released in spray and bomb modes, and contributes to immune cell mediated killing of targets (doi:10.1101/2025.01.29.635520).

l) We have applied SMAP imaging in the assessment of immune cell attack on malaria parasites inside red blood cells, an unexpected application beyond cancer (PMID: 40500441).

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Supramolecular attack particles (SMAPs) are molecular bomb shells that contain toxic molecules in their core, protected by a dense sugary shell. ATTACK has advanced the state-of-the-art by showing where SMAPs are stored in two types of white blood cells and that leukemic cells impair the ability of immune cells to make a key SMAP component.

During the past four years we have gained a better understanding of the composition of SMAPs, their release and how their killing capabilities can be improved. This was possible through the development and implementation of several new methods including a new computational strategy generating fully explicable image analysis and the enhancement of our program for automatic vesicle fusion detection. We were able to identify new key players in the pathways that regulate SMAP biogenesis. We have added to our understanding of mechanisms by which immune cells kill cancer cells and will next determine if SMAPs use the full range of mechanisms or display greater specialization.

We are on track to establish a versatile new biotechnology based on molecular bomb-shells for applications in cancer and chronic viral infection immunotherapy, and to reshape these into gentler vehicles for rebuilding damaged tissues, where distinct cargo types including key tissue building blocks can be delivered to specific locations in the body by the end of the project in 2027.

SMAPs are stored in specific lytic granules

SMAPs are molecular bombs with a sugary shell and toxic core