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Tumour growth mirrors Darwin's theory of evolution

Over the past few years, immunotherapies – treatments which harness the power of the immune system to fight cancer – have been making headlines around the world.

These powerful new weapons are exciting because once the immune system has ‘locked-on’ to a cancer cell it’s persistent and ruthless in taking it out. For patients in whom they work, immunotherapies can produce long-lasting effects. Some have even suggested they can cure certain cancers.

But the biggest challenges for immunotherapy have been identifying which molecules on the cancer cells are the best targets, as well as how to get past cancer’s defences.

For now, the immunotherapy treatments available to patients are powerful-but-blunt weapons, which in some cases can result in a number of potentially serious side effects.

What’s urgently needed are treatments that can guide immune cells to specifically attack a tumour, while leaving healthy cells alone.

And today, Cancer Research UK scientists have published a new study in the journal Science that may have uncovered the intelligence needed to precisely guide these new weapons.

But before we go into detail about what they found, and its implications for future research, let’s recap how different immunotherapies work.

Helping the immune system spot cancer

Over the years, researchers have tried many different approaches to turn the immune system against cancer, such as cutting the brakes on immune cells, flagging cancer cells for destruction, or genetically engineering a patient’s immune cells to directly target cancer cells.

Healthy T-cell

A healthy T-cell. Credit: Flickr/CC BY 2.0

But most of these depend on the immune system being able to recognise cancer cells as the true threat that they are. So how does this happen?

As we’ve written about before, almost all cells in our bodies display samples of the proteins they produce on their surface.

These small samples, called antigens, act as ‘flags’ for the immune system.

When a cell becomes damaged or infected, it changes the proteins it makes, displaying these as new antigens on its surface. Specialised immune cells, called T-cells, can then spot these antigens, releasing signals that destroy the damaged cell if the antigens aren’t looking the way they should.

The DNA faults inside cells that lead to cancer can also change how proteins ‘look’ to the immune system. So, theoretically, once the immune system recognises a cancer specific antigen, it should destroy all cancer cells that carry that flag. But this doesn’t always happen. And researchers have been working hard to find out exactly why.

Is recognition enough?

“Essentially there are two competing ideas”, says Dr Sergio Quezada, from University College London, and one of the world’s leading experts in how the immune system interacts with cancer.

If immune cells waste precious resources chasing after antigens that aren’t present on the surface of all the cancer cells then they risk missing parts of the tumour entirely

– Dr Sergio Quezada, Cancer Research UK

“One possibility is that the immune system simply needs to recognise cancer cells. Once it begins breaking open and killing tumour cells a domino effect takes place, allowing the immune system to recognise more and more ‘funny looking’ molecules.

“The other possibility is that the initial antigen that excites the immune system does matter. If immune cells waste precious resources chasing after antigens that aren’t present on the surface of all the cancer cells then they risk missing parts of the tumour entirely.”

Developing better immunotherapies is reliant on figuring out which of these ideas is true. But to answer this question would require an enormous amount of data from patients’ tumours.

Fortunately, another Cancer Research UK- funded team, working on a different challenge, have developed a set of tools that might help provide that answer.

An evolving solution

The Francis Crick Institute’s Professor Charlie Swanton is one of the world’s leading experts in the genetics behind how tumours grow and change, and the gene faults (mutations) that fuel this.

“One of the reasons why some cancers – lung cancer and melanoma in particular – are so hard to treat is because they evolve so rapidly they quickly outpace the drugs we use to stop them,” he says.

“These cancers have been exposed to many DNA damaging substances – such as cigarette smoke or UV light – and this damage gives rise to many different faults in their DNA.”

But as the data has poured in, Swanton’s team had begun to wonder whether this overwhelming complexity, which can make cancers so resistant to certain treatments, may be the very thing that reveals it to the immune system.

Immunecellsattack

A computer visualisation of immune cells attacking a complex tumour

Swanton’s team has already shown that some early DNA faults at the ‘trunk’ of a tumour’s evolutionary ‘tree’ can persist late in its development. But if these early origins of a cancer’s development are also being presented as antigens on the surface of tumour cells, they could provide an ideal target for the immune system to attack.

So Swanton and Quezada’s team’s joined forces to find out if this is the case.

We had suspected that the diversity of mutations we see in tumour evolution would be reflected by the antigens present on the cancer cells – but until now we had no proof

– Dr Nicholas McGranahan

Dr Nicholas McGranahan works in Swanton’s team, mapping how tumours evolve and change using complex software. Turning this computational firepower to analysing cancer’s immune signature was a new idea: “We have been using this type of analysis to predict what sorts of mutations are present across the tumour, so we wondered whether we could also use it to look for antigens shared on all tumour cells,” McGranahan explains.

“We had suspected that the diversity of mutations we see in tumour evolution would be reflected by the antigens present on the cancer cells – but until now we had no proof.”

To test this, they turned to a treasure trove of data called The Cancer Genome Atlas (TCGA), which records genetic data on thousands of patients who’ve been treated for cancer, alongside how they fared after treatment.

Using these data from over 200 patients with one of two different types of lung cancer (adenocarcinoma and squamous cell carcinoma) they predicted how many antigens a tumour contained, and the proportion that were common throughout the tumour.

Strikingly, in the lung adenocarcinoma patients, they saw that when the tumour cells contained many antigens that were shared across the tumour, the patients generally fared better.

But in people with squamous cell carcinoma the team didn’t find the same association. Instead, the squamous cell carcinoma cells tended not to display antigens on their surface – providing them with a potential way of escaping the immune system.

But to understand why there might be an association at all, the researchers took a closer look at tumour samples from two patients with lung cancer that had a similar smoking history.

After first running their antigen prediction analysis on the two tumour samples, the team then produced hundreds of these predicted antigens in the lab to ‘fish out’ any immune cells in the tumour samples that recognised and latched on to them.

Just three antigens were up to the job. One in the first sample and two in the second. And, crucially, each of these antigens had originally been predicted to be present on every cancer cell in the tumour sample – as the animation below explains.

So if these immune cells were capable of recognising every cell in the tumour, why didn’t they kill it?

Breaking down cancer’s defences

Clearly, these tumours contained immune cells capable of recognising the cancer cells as dangerous, but somehow the cancer was keeping them at bay.

Tumours use tricks to escape destruction by immune cells, including releasing signals that suppress immune cells. To see if these signals might be holding the immune system back from recognising the shared antigens, the team reanalysed the adenocarcinoma samples from the TCGA. Crucially, they found that tumours containing lots of antigens that were shared across the tumour also produced high levels of an immune-dampening molecule called PD-L1.

This suggests that while these cancer cells should be highly vulnerable to immune attack – because they are covered in shared antigens – they have to find a way of holding the immune system at bay to survive.

To test this idea further, the team then looked at data from patients in a US study, who’d received a checkpoint immunotherapy drug called pembrolizumab (Keytruda), which blocks the immune cells from receiving the PD-L1 ‘stop signal’.

After running their antigen prediction programme, the team then grouped the tumours into those that had many antigens on all cancer cells and those that carried lots of different tumour antigens on their surface.

Of 13 patient tumours that had many shared antigens, 12 had responded well to the immunotherapy treatment. This compared with just two out of 18 patients responding well when the team found lots of different antigens across the tumour.

160202-Immune-drugs-response-update

The analysis was based on data from this study

The picture was getting clearer. Tumours with many shared antigens attracted immune cells, which the cancer cells then had to suppress to stay alive. But if drugs were given that break through the cancer’s defences, patients whose cancers had antigens that were found across the tumour appeared to benefit the most.

So what next?

The immediate implications of this work are for researchers developing new immunotherapies. It shows that there are ‘good’ and ‘bad’ targets for immunotherapy treatments. And it strongly suggests the antigen the immune system recognises really does matter.

This is important, because many experimental treatments assume that simply showing any antigen to the immune system will be enough to wake it up. But if the target isn’t present on all the cancer cells, then the treatment risks leaving some cells behind, where they can regroup and the tumour can come back.

The next step is to work out how doctors could use the team’s prediction programmes to make better decisions over which treatments to offer patients.

Although it’s early days, it offers hope that we might just be able to turn the tide against advanced cancer – something we desperately want for our patients

– Professor Charlie Swanton, Cancer Research UK

In some cases, cancers may be hiding the ‘flags’ that immune cells recognise, so other treatments may need to be explored.

But if scientists can harness the immune cells that do recognise these targets it could lead to new treatments.

For Swanton, the study reveals a welcome weakness behind cancer’s sometimes baffling complexity.

“Since the true genetic complexity of a growing tumour began to be revealed a few years ago, we’ve all been scratching our heads trying to work out a way round it,” he says.

But he now believes we are beginning to find ways to “develop truly effective treatments for advanced disease that exploit the underlying order in the chaos”.

“It’s incredibly exciting,” he adds, “and although it’s early days, it offers hope that we might just be able to turn the tide against advanced cancer – something we desperately want for our patients.”

Swanton, Quezada and their teams are now working to turn this idea into something that could be applied to many more cancers, finding unique targets on all cancer cells and not the healthy cells.

Immunotherapy is an incredibly exciting weapon against cancer – as recent headlines make clear.

Thanks to the combined ingenuity of two of our teams of cancer researchers, we may have found the tools necessary to give immunotherapy the precision guidance that patients so desperately need.

Alan

Reference

McGranahan, et al., (2016). Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. DOI: 10.1126/science.aaf1490

Comments

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lindquist70 August 27, 2016

I don’t agree Sincerely, Brenna

Najua Diba July 9, 2016

I want the doctor who is the responsible to the search to pay litlle attention what I will say here: I believe that cancer should be look at in his own envirement because they suffer mutations along their grow. It means that the cancer don’t need to be remove from the paciente , but with the modern tecnology the doctor will see it on the body to discover the principal mother cell who starts the process. Doing it, with microscop and câmara , the doctor will inject in this mother cell the mix of magnesium, potássio and zinco.In the same portion, that is very little in according to the mass of the mother cell. If câncer is removed with operation, it spreads. The point is to kill the mother cell. If the salts minerals don’t work apply to the mother cell another medicine that you think will.
I call it Joao Guethes method. I am Brazilian, and if its work, Glory be to God and health for thousands people. And if it works, please tell me in order to send a friend to be cure. With respect, Najua Diba

David Whitehead June 5, 2016

After reading the information published I think that you are on the right track, and after some tweaking here and there you should be onto a winner. I have a question for the team. I have SCLC (left) T4 NO MO which was picked up in April 2015, I had 4 sessions of chemo and 35 sessions of radiotherapy. I had a lung scan done after my second session of chemo and was told that the cancer had shrunk. I had another scan done after my radiotherapy and was told that the cancer had grown. why should it have grown after radiotherapy? I was told before my treatment that they would not operate to remove the growth as they thought it may be impinging on the Pulmary Artery, but the scan showed that it was not, I have asked if it would be possible to operate to either remove the cancer or possibly the lung and was told that surgery was not possible and I must continue with chemo even though it may not slow down the growth. Any suggestions as I am open to all possibilities.

Alan May 14, 2016

May this be a moment in time that we can look back on and say these amazing scientists and their teams, along with everybody’s support, has put a stamp on the medical treatment timeline. Thank you to everybody involved. I lost my father, who was my best friend, so for the medical profession, scientists, current and any future fighters, God speed!

GITA April 25, 2016

THIS A VERY GOOD NEWS ,BUT WHO WANTS TO KNOW MORE PLEASE WATCH THE TRUTH ABOUT CANCER,THERE ARE SO MANY WAYS TO BEAT CANCER,IT GIVES ME HOPE,CAUSE I AM CANCER GENE CARER.

RolAnd March 27, 2016

Well Dan and God bless I hope one day it’ will be finish badnes to peapole

Eileen March 26, 2016

Fascinating reading wonderful to hear so many dedicated people are doing such amazing research and continuing to find out sources of and workings of so many cancers. The world owes so much to so few. Keep up the good work!!!

Ann Purslow March 25, 2016

Excellent report easy for people who have very little science or medical knowledge.

Susan Chapman March 25, 2016

Thank you cancer researchers for giving hope to all of us who live with cancer. I hope and pray this is the breakthrough we have all been waiting for.

Adam Foxley March 24, 2016

Our small company has donated £50 per month, every month for many years. We do it in the name of our employees and the many friends and family who are afflicted with cancer. But we also do this in self-interest. And proud to say so. By helping to save ourselves, we help to save others. If everyone did this, cancer would already be beaten. It is the last great disease to mass-kill humans. And not just people at very advanced ages but young people in their 50’s, 60’s and 70’s who are full of life and dreams. Why the world can get together for climate change but not for cancer is beyond me. Imagine the cancer research budget if every government halved defence spending. Instead of 2% of world GDP, only 1%. That would save 750 billion dollars a year. If there would be one benefit from living in a totally globalised world of call centres and sameness, it would be the world uniting to equally halve defense budgets and spending everything on Cancer Research. Crazy? Why don’t people use Twitter and other social media for the real the power it has.

Robert Pamment March 24, 2016

A fascinating read and a giant step for mankind; the researchers deserve so much credit.

Nicola Nissen March 24, 2016

I think it is an amazing finding and I believe we will eventually beat it. Pray something else doesn’t turn up to be as bad.

Ray Butler March 24, 2016

wonderful article. Please let this all happen in time to cure my lovely wife

Liz Adams March 24, 2016

Well done Cancer Research for such ground breaking research. It feels like we are within reach of our goal, to see cancer off. Warm thanks to the team.

Linda Penney March 24, 2016

So encouraging to hear the great progress being made in understanding and treating cancer, especially new approaches to add to radiotherapy and chemotherapy. Gives hope to those of us in remission and underlines how vital it is to ensure fundraising efforts continue to support the research efforts of those working on our behalf.

roland March 24, 2016

This is the most progressive and heartening news that I have read in the 32 years since my wife died of breast cancer. I pray that an end is in sight for all sufferers of this dreadful disease.

Marilyn March 24, 2016

It seems that a cure is closer thanks to these dedicated scientists. I’m sure many will feel uplifted by these facts, including myself. Praise the day the ‘C’ word is non-existent .

Jenny miln March 24, 2016

An excellent article -thank you

Diana gibson March 22, 2016

Today we were told my 52yrs old son-I law has just 3months left to live my daughter is 47yrs old they have only been married 5yrs please tell me a miracale can happen

Kathryn Sharp March 7, 2016

Wonderfully written and wonderfully informative article. Actually heartening. Shared on Facebook. I had breast cancer and a double mastectomy October 2002. I have family and friends that have died from cancer and done are in the battle now—on the front lines.

Steve Mainwaring March 5, 2016

One in three of us will be diagnosed with cancer…its in all our interests to support the cancer research charities by donating regular amounts (however small)

Jeanne - Marie March 4, 2016

This will give hope to millions praying for success soon. JL

Stephanie March 4, 2016

This is very nicely explained. Very good article that gets to the crux of the issue of what the researchers found. I really like that the author took time to explain the key points and did not rush over them.

Mario March 4, 2016

Is there a way to share these story’s Etc eg on facebook