From NHS

Scientists improved the immune system of mice

The media is awash with news of a breakthrough that is “turbocharging the immune system to kill all cancers” (The Daily Telegraph) and a “game-changing new way to fight cancer” (The Independent).

Both of these vivid headlines are debatable – the first because the technique has only been looked at in one type of cancer, and the second because it has only been examined in lab mice.

Researchers were actually looking at a way to overcome “exhaustion” of the body’s immune system when its killer cells (called CD8 T cells) have too much to deal with. They wanted to find out how to increase the number of these killer cells, and memory cells that help the immune system “remember” cancers and viruses.

The researchers used genetic techniques in mice to study CD8 T cells. They discovered a protein, lymphocyte expansion molecule (LEM), which helps increase the number of CD8 T cells, improving the mice’s ability to fight viruses or cancer cells. The LEM protein is a new discovery, and the researchers hope they can produce treatments for human diseases based on it.

Discovery aside, research on this protein is at its first stage. A balance of the beneficial and harmful effects of boosting the immune system with this protein would need to be struck before it can start being tested on people.

So we now know more about the human immune system, but it is – as is often the case – too early to say if it will lead to a truly “game-changing” treatment for cancer.
Where did the story come from?

The study was carried out by researchers from Imperial College London, Queen Mary University of London, Harvard Medical School, and ETH Zurich, a specialist science university in Switzerland.

The study received various sources of funding, including from the Wellcome Trust, Cancer Research UK, and the US National Institutes of Health.

It was published in the peer-reviewed journal, Science.

The news stories give representative coverage of this laboratory study overall, but their headlines talking about a “breakthrough” give premature hopes about research that is still in the very early stages.

The Mail Online’s estimate that a drug based on the findings “could be tested on humans in three years” appears to be based on this press release from Imperial College London. However, it would be many years of further research before any treatment becomes widely available.

The press release, which describes “boosting immunity to viruses and cancer”, is likely the basis for the “turbocharging” and “game-changing” metaphors used in much of the media coverage.
What kind of research was this?

This laboratory and animal research examined the workings of the immune system, specifically looking at CD8 T cells. T cells are a type of white blood cell (lymphocytes) that play a key role in defending the body against infection from foreign organisms such as viruses and bacteria.

T cells also destroy abnormal or cancerous cells. The T cells that have this “killing” ability are sometimes called killer T cells, or cytotoxic T cells. Because they carry a receptor for the CD8 protein, these particular cells are called cytotoxic CD8 T cells.

But the very fact humans get infections and cancer is evidence that the CD8 T cell immunity is a bit flawed. A possible reason for this flaw is that because there are so many virally infected or cancerous cells, the CD8 T cells may in some way become inactivated – a kind of “immune exhaustion”.

This exhaustion causes a failure of the immune response in the short term, but also hinders the development of “memory” CD8 T cells. These are T cells that “remember” how to recognise abnormal cells for future immune response.

In this study, the researchers looked at the immune response of genetically mutated mice infected with a virus. They wanted to see whether they could identify ways to encourage more cytotoxic CD8 T cells and memory cells to grow.
What did the research involve?

The research involved both normal mice and mice carrying different genetic mutations to see whether some of the mutant mice had a better immune response.

The mice were infected with a virus called lymphocytic choriomeningitis virus (LCMV C13). This is said to be an established animal model for chronic viral infection in humans. It results in a very high level of virus in the body, causing “immune exhaustion” of CD8 cells and blocking memory cell development.

About a week after infecting the mice, levels of cytotoxic CD8 cells and memory cells were measured to see which mice were producing more of them.

The researchers furthered their study of viral infection by also looking at the response when mice were given cancer (melanoma) cells.

In the mice with enhanced immune response, the researchers then identified what gene was causing this heightened response.
What were the basic results?

The researchers found a particular type of mutant mouse (called “Retro” mutant mice) had increased CD8 T cell levels ten times that of normal mice. These cells had increased virus-killing ability when studied in the lab.

However, the researchers found all Retro mice died two weeks after infection, whereas the normal mice survived the infection. They thought this was because the increased immune response in the Retro mice led to a fatal breakdown of the blood vessels.

The Retro mice also demonstrated increased production of CD8 memory cells. When mice were injected with a second dose of the LCMV virus later on, the Retro mice again had a very enhanced CD8 T cell response compared with the normal mice.

Similarly, when injected with melanoma cells, the Retro mice demonstrated three times higher CD8 T cell levels, and four times fewer tumours, compared with normal mice injected with melanoma.

The Retro mice were found to have a mutation in a gene that codes for a protein called lymphocyte expansion molecule (LEM). The researchers confirmed that this gene and protein were involved in the enhanced immunity in a further study, where mice were genetically engineered to lack this gene variant or the cellular activity of the protein was blocked.

Researchers also identified the human equivalent of the LEM protein and found it was produced in higher levels in human T cells responding to infection. Increasing the amount of LEM the human T cells were making in the lab caused them to divide and produce more T cells.
How did the researchers interpret the results?

The researchers say they have “discover[ed] LEM at the heart of a pathway that, when up-regulated, not only restores CD8 T cell immunity to chronic viral infection and tumour challenge, but also increases memory cell development”.

They say that, “LEM therapy has the potential to both globally expand CD8 T cells”.
Conclusion

This laboratory study in mice has looked at how CD8 T cell immunity might be enhanced. Researchers hoped to find ways to increase the numbers of “killing” cells that can destroy infected or abnormal cells and avoid a state of “immune exhaustion”, which leads to humans succumbing to infection or the progression of cancer.

Studying normal and genetically mutated mice, they identified a previously overlooked protein they called LEM, which is involved in increasing the numbers of these cells. The researchers hope it could one day lead to the production of LEM therapy.

While they do not specify treatment use in their research article, an accompanying press release spells out that they hope the research will be used to develop cancer treatments.

The study is at a very early stage and many questions remain unanswered. The main problem is that nobody appears to have looked into the role of LEM protein in humans yet.

Another problem that can’t be ignored is that all the Retro mice died after infection as a result of their greatly enhanced CD8 T cell proliferation. This shows there is a delicate balance to be struck in enhancing LEM activity and immune cell proliferation, while keeping side effects to a minimum.

The study in mice is, so far, also limited to the study of a particular virus and melanoma cancer cells. We don’t yet know whether the same CD8 T cell proliferation would be seen with all infections or all cancer. It’s also not clear whether the levels of proliferation seen would completely remove or prevent viral infection or cancer.

Overall, the research genuinely furthers our understanding of how the immune system fights infections and cancer, but it is too early to know if this will lead to a treatment breakthrough for cancer.

Analysis by Bazian. Edited by NHS Choices.

For more on this story go to: http://www.nhs.uk/news/2015/04April/Pages/discovery-could-boost-immune-systems-cancer-fighting-ability.aspx

Related story:

Scientists discover protein that boosts immunity to viruses and cancer

By Sam Wong From Imperial College London 16 April 2015

Scientists have discovered a protein that plays a central role in promoting immunity to viruses and cancer, opening the door to new therapies.

Experiments in mice and human cells have shown that the protein promotes the proliferation of cytotoxic T cells, which kill cancer cells and cells infected with viruses. The discovery was unexpected because the new protein had no known function and doesn’t resemble any other protein.

Researchers from Imperial College London who led the study are now developing a gene therapy designed to boost the infection-fighting cells, and hope to begin human trials in three years.

The study also involved researchers at Queen Mary University of London, ETH Zurich and Harvard Medical School. Their discovery, which has been six years in the making, is reported today in the journal Science.

Cytotoxic T cells are an important component of the immune system, but when faced with serious infections or advanced cancer, they are often unable to proliferate in large enough quantities to fight the disease.

By screening mice with genetic mutations, the Imperial team discovered a strain of mice that produced 10 times as many cytotoxic T cells when infected with a virus compared with normal mice. These mice suppressed the infection more effectively, and were more resistant to cancer. They also produced more of a second type of T cells, memory cells, enabling them to recognise infections they have encountered previously and launch a rapid response.
“If all goes well, we hope to be ready to carry out human trials in about three years.”

– Professor Philip Ashton-Rickardt

Department of Medicine

The mice with enhanced immunity produced high levels of a hitherto unknown protein, which the researchers named lymphocyte expansion molecule, or LEM. They went on to show that LEM modulates the proliferation of human T cells as well as in mice.

The researchers now aim to develop a gene therapy designed to improve immunity by boosting the production of LEM. With the support of Imperial Innovations, the technology commercialisation company for the College, the researchers have filed two patents. A company called ImmunarT has been formed with the aim of commercialising the technology.

Professor Philip Ashton-Rickardt from the Section of Immunobiology in the Department of Medicine at Imperial, who led the study, said: “Cancer cells have ways to suppress T cell activity, helping them to escape the immune system. Genetically engineering T cells to augment their ability to fight cancer has been a goal for some time and techniques for modifying them already exist. By introducing an active version of the LEM gene into the T cells of cancer patients, we hope we can provide a robust treatment for patients.

“Next we will test the therapy in mice, make sure it is safe and see if it can be combined with other therapies. If all goes well, we hope to be ready to carry out human trials in about three years.”

Dr Claudio Mauro, who led the research from the Centre for Biochemical Pharmacology, based within Queen Mary University of London’s William Harvey Research Institute, said: “This study has identified the novel protein LEM and unlocked an unexpected way of enhancing the ability of our immune system to fight viruses or cancers. This is based on the ability of the protein LEM to regulate specific energy circuits, and particularly mitochondrial respiration, in a subset of white blood cells known as cytotoxic T cells. This discovery has immediate consequences for the delivery of innovative therapeutic approaches to cancer. Its ramifications, however, are far greater as they can help explaining the biological mechanisms of widespread human diseases involving altered immune and inflammatory responses. These include chronic inflammatory and autoimmune disorders, such as atherosclerosis and rheumatoid arthritis.”

The research was funded by the Medical Research Council, the Wellcome Trust and the British Heart Foundation.

Dr Mike Turner, Head of Infection and Immunobiology at The Wellcome Trust, said: “The discovery of a protein that could boost the immune response to not only cancer, but also to viruses, is a fascinating one. Further investigation in animal models is needed before human trials can commence, but there is potential for a new type of treatment that capitalises on the immune system’s innate ability to detect and kill abnormal cells.”
Reference

Okoye et al. ‘The protein LEM promotes CD8+ T cell immunity through effects on mitochondrial respiration.’ Science, 16 April 2015. DOI: 10.1126/science.aaa7516

IMAGE: Cytotoxic T cells with the protein LEM stained.

SOURCE: http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_16-4-2015-14-51-47