Periodic Reporting for period 2 - ATTACK (Analysis of the T cell’s Tactical Arsenal for Cancer Killing)
Período documentado: 2022-11-01 hasta 2024-04-30
About 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-destruct 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.
The toxins open holes in the tumour cells and induce a self-destruct 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.
During the past two years, the ATTACK superlab has made substantial progress in deciphering the origin of SMAPs and their biogenesis. Furthermore, it investigated how cancer cells fight back against the killer white blood cell attack. Our major achievements are listed below.
a) We identified two possible trafficking pathways for the regulation of SMAP production in cells.
b) We succeeded in identifying the storage sites for the spray-like and bomb-like release of cells destroying molecules (PMID: 35210420).
c) These storage sites are referred to as “granules” and differ in diameter, shape and composition, but also in the type (spray vs bomb) with which their cytotoxic contents are released (PMID: 35210420).
d) We have isolated SMAPs from a natural killer cell line, which is very similar to the composition of SMAPs released from killer T cells (doi: 10.1002/jex2.74).
e) Cancer cells respond to killer T cell attack within seconds and create a defensive line that protects the core of solid tumours, a challenge facing immunotherapy (PMID: 35171665).
f) Initiated during the Covid-19 pandemic, ATTACK contributed to our fundamental understanding of SARS-Cov2 mediated immune evasion by demonstrating that the spike protein inhibits immunological synapse formation, and thus, SMAP delivery to infected cells (PMID: 36378226).
g) 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 (DOI: 10.48550/arXiv.2303.14762).
h) We have collaborated on publications that help explain SMAPs to the scientific community, published detailed methods to enable the work of other scientists in this area and have published original research on SMAPs (PMID: 37325629; 35514977; 35592329; 37106198; 37106201).
i) ATTACK maintains an up-to-date web site (https://supramolecular-attack-particles.eu) to help communicate discoveries to the public.
a) We identified two possible trafficking pathways for the regulation of SMAP production in cells.
b) We succeeded in identifying the storage sites for the spray-like and bomb-like release of cells destroying molecules (PMID: 35210420).
c) These storage sites are referred to as “granules” and differ in diameter, shape and composition, but also in the type (spray vs bomb) with which their cytotoxic contents are released (PMID: 35210420).
d) We have isolated SMAPs from a natural killer cell line, which is very similar to the composition of SMAPs released from killer T cells (doi: 10.1002/jex2.74).
e) Cancer cells respond to killer T cell attack within seconds and create a defensive line that protects the core of solid tumours, a challenge facing immunotherapy (PMID: 35171665).
f) Initiated during the Covid-19 pandemic, ATTACK contributed to our fundamental understanding of SARS-Cov2 mediated immune evasion by demonstrating that the spike protein inhibits immunological synapse formation, and thus, SMAP delivery to infected cells (PMID: 36378226).
g) 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 (DOI: 10.48550/arXiv.2303.14762).
h) We have collaborated on publications that help explain SMAPs to the scientific community, published detailed methods to enable the work of other scientists in this area and have published original research on SMAPs (PMID: 37325629; 35514977; 35592329; 37106198; 37106201).
i) ATTACK maintains an up-to-date web site (https://supramolecular-attack-particles.eu) to help communicate discoveries to the public.
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 isolated SMAPs kill cancer cells in the test tube and in pre-clinical cancer models.
The frontier for the next stage of the project will be to better understand how SMAPs kill cancer cells, how they are released from killer white blood cells, how the bomb is detonated to release the toxic core in tumour cells and to improve the ability of SMAPs to latch onto cancerous cells such that their destructive power can be focused. We will also need to determine if we can produce enough SMAPs for therapeutic applications using bioreactor technologies. Our understanding of SMAPs will further be tested by our ability to make synthetic SMAP out of defined building blocks- including an understanding of how the payload is concentrated and how the sugary shell is assembled. We will also need to understand the stability of natural and synthetic SMAPs and how to build in safety features, such as the ability to turn them off if they were to start to cause harm in a patient.
At the end of the project, we hope to have laid the groundwork for 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.
The frontier for the next stage of the project will be to better understand how SMAPs kill cancer cells, how they are released from killer white blood cells, how the bomb is detonated to release the toxic core in tumour cells and to improve the ability of SMAPs to latch onto cancerous cells such that their destructive power can be focused. We will also need to determine if we can produce enough SMAPs for therapeutic applications using bioreactor technologies. Our understanding of SMAPs will further be tested by our ability to make synthetic SMAP out of defined building blocks- including an understanding of how the payload is concentrated and how the sugary shell is assembled. We will also need to understand the stability of natural and synthetic SMAPs and how to build in safety features, such as the ability to turn them off if they were to start to cause harm in a patient.
At the end of the project, we hope to have laid the groundwork for 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.