̽��ֱ�� of Cambridge - Gillian Griffiths

Mito warriors: how T cell assassins reload their weapons to kill and kill again

cjb250 — Thu, 14 Oct 2021 18:00:18 +0000

Cytotoxic T cells are specialist white blood cells that are trained by our immune system to recognise and eliminate threats – including tumour cells and cells infected with invading viruses, such as SARS-CoV-2, which causes COVID-19. They are also at the heart of new immunotherapies that promise to transform cancer treatment.

Professor Gillian Griffiths from the Cambridge Institute for Medical Research, who led the research, said: “T cells are trained assassins that are sent on their deadly missions by the immune system. There are billions of them in our blood, each engaged in a ferocious and unrelenting battle to keep us healthy.

“Once a T cell has found its target, it binds to it and releases its toxic cargo. But what is particularly remarkable is that they are then able to go on to kill and kill again. Only now, thanks to state-of-the-art technologies, have we been able to find out how they reload their weapons.”

Today, in a study published in Science, the team have shown that the refuelling of T cells’ toxic weapons is regulated by mitochondria. Mitochondria are often referred to as a cell’s batteries as they provide the energy that power their function. However, in this case the mitochondria use an entirely different mechanism to ensure the killer T cells have sufficient ‘ammunition’ to destroy their targets.

Professor Griffiths added: “These assassins need to replenish their toxic payload so that they can keep on killing without damaging the T cells themselves. This careful balancing act turns out to be regulated by the mitochondria in T cells, which set the pace of killing according to how quickly they themselves can manufacture proteins. This enables killer T cells to stay healthy and keep on killing under challenging conditions when a prolonged response is required.”

Understanding the details of this basic process could ultimately help in the long-term scientific goal of designing and engineering T cells that are better at killing cancer cells, say the researchers.

To accompany the study, Professor Griffiths and colleagues have released footage showing killer T cells as they hunt down and eliminate cancer cells.

One teaspoon full of blood alone is believed to have around 5 million T cells, each measuring around 10 micrometres in length, about a tenth the width of a human hair. ̽��ֱ��cells, seen in the video as red or green amorphous ‘blobs’, move around rapidly, investigating their environment as they travel.

When a T cell finds an infected cell or, in the case of the film, a cancer cell, membrane protrusions rapidly explore the surface of the cell, checking for tell-tale signs that this is an uninvited guest. ̽��ֱ��T cell binds to the cancer cell and injects poisonous ‘cytotoxin’ proteins down special pathways called microtubules to the interface between the T cell and the cancer cell, before puncturing the surface of the cancer cell and delivering its deadly cargo.

̽��ֱ��research was funded by Wellcome.

Reference
Lisci, M et al. Mitochondrial translation is required for sustained killing by cytotoxic T cells. Science; 14 Oct 2021; DOI: 10.1126/science.abe9977

Cambridge researchers have discovered how T cells – an important component of our immune system – are able to keep on killing as they hunt down and kill cancer cells, repeatedly reloading their toxic weapons.

T cells are trained assassins that are sent on their deadly missions by the immune system. There are billions of them in our blood, each engaged in a ferocious and unrelenting battle to keep us healthy

Gillian Griffiths

T-cell assassins captured on film hunting down cancer cells and ‘reloading’ to kill again

Killer T cell attacking a cancer cell

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Synthetic organs, nanobots and DNA ‘scissors’: the future of medicine

lw355 — Thu, 12 Oct 2017 08:00:43 +0000

In a new film to coincide with the recent launch of the Cambridge Academy of Therapeutic Sciences, researchers discuss some of the most exciting developments in medical research and set out their vision for the next 50 years.

Professor Jeremy Baumberg from the NanoPhotonics Centre discusses a future in which diagnoses do not have to rely on asking a patient how they are feeling, but rather are carried out by nanomachines that patrol our bodies, looking for and repairing problems. Professor Michelle Oyen from the Department of Engineering talks about using artificial scaffolds to create ‘off-the-shelf’ replacement organs that could help solve the shortage of donated organs. Dr Sanjay Sinha from the Wellcome Trust-MRC Stem Cell Institute sees us using stem cell ‘patches’ to repair damaged hearts and return their function back to normal.

Dr Alasdair Russell from the Cancer Research UK Cambridge Institute describes how recent breakthroughs in the use of CRISPR-Cas9 – a DNA editing tool – will enable us to snip out and replace defective regions of the genome, curing diseases in individual patients; and lawyer Dr Kathy Liddell, from the Cambridge Centre for Law, Medicine and Life Sciences, highlights how research around law and ethics will help to make gene editing safe.

Professor Gillian Griffiths, Director of the Cambridge Institute for Medical Research, envisages us weaponising ‘killer T cells’ – important immune system warriors – to hunt down and destroy even the most evasive of cancer cells.

All of these developments will help transform the field of medicine, says Professor Chris Lowe, Director of the Cambridge Academy of Therapeutic Sciences, who sees this as an exciting time for medicine. New developments have the potential to transform healthcare “right the way from how you handle the patient to actually delivering the final therapeutic product - and that’s the exciting thing”.

Read more about research on future therapeutics in Research Horizons magazine.

Nanobots that patrol our bodies, killer immune cells hunting and destroying cancer cells, biological scissors that cut out defective genes: these are just some of technologies that Cambridge researchers are developing which are set to revolutionise medicine in the future.

̽��ֱ��Future of Medicine

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

̽��ֱ��self-defence force awakens

cjb250 — Tue, 04 Jul 2017 16:50:17 +0000

An army of cells constantly patrols within us, attacking anything it recognises as foreign, keeping us safe from invading pathogens. But sometimes things go wrong: the soldiers mistake benign cells for invaders, turning their friendly fire on us and declaring war.

̽��ֱ��consequences are diseases like multiple sclerosis (MS), asthma, inflammatory bowel disease, type 1 diabetes and rheumatoid arthritis – diseases that are increasing at an alarming rate in both the developed and developing worlds.

Cambridge will be ramping up the fight against immune-mediated and inflammatory diseases with the opening next year of the Cambridge Institute of Therapeutic Immunology and Infectious Disease, headed by Professor Ken Smith. ̽��ֱ��Institute will work at the interface between immunity, infection and the microbiome (the microorganisms that live naturally within us). “We’re interested in discovering fundamental mechanisms that can turn the immune system on or off in different contexts, to modify, treat or prevent both inflammatory and infectious diseases,” says Smith.

But while diseases such as Crohn’s and asthma have long been understood to be a consequence of friendly fire, scientists are starting to see this phenomenon give rise to more surprising conditions, particularly in mental health.

In 2009, Professor Belinda Lennox, then at Cambridge and now at Oxford, led a study that showed that 7% of patients with psychoses tested positive for antibodies that attacked a particular receptor in the brain, the NMDA receptor. This blocked a key neurotransmitter, affecting communication between nerve cells and causing the symptoms.

Professor Alasdair Coles from Cambridge’s Department of Clinical Neurosciences is working with Lennox on a trial to identify patients with this particular antibody and reverse its effects. One of their treatments involves harnessing the immune system – weaponising it, one might say – to attack rogue warriors using rituximab, a monoclonal antibody therapy that kills off B-cells, the cells that generate antibodies.

“You can make monoclonal antibodies for experimental purposes against anything you like within a few days,” explains Coles. “In contrast, to come up with a small molecule – the alternative sort of drug – takes a long, long time.”

̽��ֱ��first monoclonal antibody to be made into a drug, created here in Cambridge, is called alemtuzumab. It targets both B- and T-cells and has been used in a variety of autoimmune diseases and cancers. Its biggest use is in MS, where it eliminates the rogue T- and B-cells that attack the protective insulation (myelin sheath) around nerve fibres. Licensed in Europe in 2013 and approved by NICE in 2014, it has now been used in tens of thousands of MS patients.

As well as treating diseases caused by the immune system, antibody therapies are now widely used to treat cancer. And, as Professor Gillian Griffiths, Director of the Cambridge Institute for Medical Research, explains, antibody-producing cells are not the only immune cells that can be weaponised.

“T-cells are also showing great promise,” she says. “They are the body’s serial killers, patrolling, identifying and destroying infected and cancer cells with remarkable precision and efficiency.”

But cancer cells are able to trick T-cells by sending out a ‘don’t kill’ signal. Antibodies that block these signals, which have become known as ‘checkpoint inhibitors’, are proving remarkably successful in cancer therapies. “My lab focuses on what tells a T-cell to kill, and how you make it a really good killer, using imaging and genetic approaches to understand how these cells can be fine-tuned,” Griffiths explains. “This has revealed some novel mechanisms that play key roles in regulating killing.”

A second, more experimental, approach uses souped-up cells known as chimeric antigen receptor (CAR) T-cells programmed to recognise and attack a patient’s tumour.

Neither approach is perfect: antibody therapies can dampen down the entire immune system, causing secondary problems, while CAR T-cell therapies are prohibitively expensive as each CAR T-cell needs to be programmed to suit an individual. But, says Griffiths, “the results to date from both approaches are really rather remarkable”.

One of the problems that’s dogged immunotherapy trials is that T-cells only have a short lifespan. Most of the T-cells transplanted during immunotherapy are gone within three days, nowhere near long enough to defeat the tumour.

This is where Professor Randall Johnson comes in. He’s been working with a molecule (2-hydroxyglutarate), which he says has “become trendy of late”. It’s an ‘oncometabolite’, believed to be responsible for making cells cancerous, which is why pharmaceutical companies are trying to inhibit its action. Johnson has taken the opposite approach.

He’s shown that a slightly different form of the molecule plays a critical role in T-cell function: it can turn them into renewable cells that hang around for a long time and can reactivate to combat cancer. Increasing the levels of this molecule in T-cells makes them stay around longer and be much better at destroying tumours. “Rather than creating killer T-cells that are active from the start, but burn out very quickly, we’re creating an army of cells that can stay quiet for a long time, but will go into action when necessary.”

This counterintuitive approach caught the attention of Apollo Therapeutics, who recognised the enormous promise and has invested in Johnson’s work, which he carried out in mice, to see if it can be applied to humans.

But T-cells face other problems, particularly in pancreatic cancer, explains Professor Duncan Jodrell from the Cancer Research UK Cambridge Institute, which is why immunotherapy against these tumours has so far failed. ̽��ֱ��problem with pancreatic cancer is that ‘islands’ of tumour cells sit in a ‘sea’ of other material, known as stroma. As Jodrell and colleagues have shown, it’s possible for T-cells to get into the stroma, but they go no further. “You can rev up your T-cells, but they just can’t get at the tumour cells.” They are running a study that tries to overcome this immune privilege and allow the T-cells to get to the tumour cells and attack them.

Tim Eisen, Professor of Medical Oncology at Cambridge and Head of the Oncology Translational Medicine Unit at AstraZeneca, believes we can expect great advances in cancer treatment from optimising and, in some cases, combining existing checkpoint inhibitor approaches.

Eisen is working with the Medical Research Council to trial checkpoint inhibitor antibody therapies as a complement – ‘adjuvant’ – to surgery for kidney cancer. Once the kidney is removed, the drug is used to destroy stray tumour cells that have remained behind. But even antibody therapies, which are now widely used within the NHS, are not universally effective and can cause serious complications. “One of the most important things for us to focus on now is which immunotherapeutic drug or particular combination of drugs might be effective in destroying tumour cells and be well tolerated by the patient.”

T-cell therapies – and, in particular, CAR T-cell therapies – are “very exciting, futuristic and experimental,” he says, “but they’re going to take some years to come in as standard therapy.”

̽��ֱ��problem is how to make them cost-effective. “It’s never going to be easier to engineer an individual person’s T-cells than it is to take a drug off the shelf and give it to them,” he says. “ ̽��ֱ��key is going to be whether you can industrialise production. But I’m very optimistic about our ability to re-engineer processes and make it available for people in general.”

We may soon see an era, then, when our immune systems become an unstoppable force for good.

Our immune systems are meant to keep us healthy, but sometimes they turn their fire on us, with devastating results. Immunotherapies can help defend against this ‘friendly fire’ – and even weaponise it in our defence.

T-cells are the body’s serial killers, patrolling, identifying and destroying infected and cancer cells with remarkable precision and efficiency.

Gillian Griffiths

̽��ֱ��moment when a T-cell kills

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Body’s ‘serial killers’ captured on film destroying cancer cells

cjb250 — Tue, 19 May 2015 08:48:01 +0000

In a study published today in the journal Immunity, a collaboration of researchers from the UK and the USA, led by Professor Gillian Griffiths at the ̽��ֱ�� of Cambridge, describe how specialised members of our white blood cells known as cytotoxic T cells destroy tumour cells and virally-infected cells. Using state-of-the-art imaging techniques, the research team, with funding from the Wellcome Trust, has captured the process on film.

“Inside all of us lurks an army of serial killers whose primary function is to kill again and again,” explains Professor Griffiths, Director of the Cambridge Institute for Medical Research. “These cells patrol our bodies, identifying and destroying virally infected and cancer cells and they do so with remarkable precision and efficiency.”

There are billions of T cells within our blood – one teaspoon full of blood alone is believed to have around 5 million T cells, each measuring around 10 micrometres in length, about a tenth the width of a human hair. Each cell is engaged in the ferocious and unrelenting battle to keep us healthy. ̽��ֱ��cells, seen in the video as orange or green amorphous ‘blobs’ move around rapidly, investigating their environment as they travel.

When a cytotoxic T cell finds an infected cell or, in the case of the film, a cancer cell (blue), membrane protrusions rapidly explore the surface of the cell, checking for tell-tale signs that this is an uninvited guest. ̽��ֱ��T cell binds to the cancer cell and injects poisonous proteins known as cytotoxins (red) down special pathways called microtubules to the interface between the T cell and the cancer cell, before puncturing the surface of the cancer cell and delivering its deadly cargo.

“In our bodies, where cells are packed together, it’s essential that the T cell focuses the lethal hit on its target, otherwise it will cause collateral damage to neighbouring, healthy cells,” says Professor Griffiths. “Once the cytotoxins are injected into the cancer cell, its fate is sealed and we can watch as it withers and dies. ̽��ֱ��T cell then moves on, hungry to find another victim.”

̽��ֱ��researchers captured the footage through high-resolution 3D time-lapse multi-colour imaging, making use of both spinning disk confocal microscopy and lattice light sheet microscopy. These techniques involves capturing slices through an object and ‘stitching’ them together to provide the final 3D images across the whole cell. Using these approaches the researchers have managed to elucidate the order the events leading to delivery of the lethal hit from these serial killers.

Reference
Ritter, AT et al. Actin depletion initiates events leading to granule secretion at the immunological synapse. Immunity; 19 May 2015

A dramatic video has captured the behaviour of cytotoxic T cells – the body’s ‘serial killers’ – as they hunt down and eliminate cancer cells before moving on to their next target.

Inside all of us lurks an army of serial killers whose primary function is to kill again and again

Gillian Griffiths

Killer T Cell: ̽��ֱ��Cancer Assassin

Gillian Griffiths/Jonny Settle

Killer T-Cell

Yes

Licence type:

Attribution