Tumors contain the seeds of their own destruction

March 03, 2016

SCIENTISTS have made a groundbreaking discovery in understanding how the genetic complexity of tumours can be recognised and exploited by the immune system, even when the disease is at its most advanced stages.

The findings, by researchers funded by Cancer Research UK and the Rosetrees Trust, could guide future immunotherapies and improve the way existing immunotherapy drugs are used.

As a tumour develops, the diversity of its genetic faults can be flagged on the cancer cell surface, as unique mutations appear in different parts of the tumour.

Crucially, by analysing data from hundreds of patients from previous studies, researchers found that some of these flags - known as antigens - represent the very earliest mutations of the disease and are displayed on all cells in the tumour, rather than a subset of tumour cells.

Then in the lab, they isolated specialised immune cells, called T-cells, from samples of two patients with lung cancer that can recognise these common flags present on every tumour cell.

Although they have the potential to wipe out all cancerous cells within the tumour, these potent immune cells are switched off by the tumour's defences.

This research paves the way for therapies that specifically activate these T cells to target all the tumour cells at once based on the disease's genetic signature. In the future, scientists could exploit this by developing a therapeutic vaccine to activate T-cells, or harvesting, growing and administering T-cells back into the patient that recognise the antigens common to every cancer cell.

Dr Sergio Quezada, co-author of the study, Cancer Research UK scientist and head of the Immune Regulation and Cancer Immunotherapy lab at UCL Cancer Institute, said: "The body's immune system acts as the police trying to tackle cancer, the criminals. Genetically diverse tumours are like a gang of hoodlums involved in different crimes - from robbery to smuggling. And the immune system struggles to keep on top of the cancer - just as it's difficult for police when there's so much going on.

"Our research shows that instead of aimlessly chasing crimes in different neighbourhoods, we can give the police the information they need to get to the kingpin at the root of all organised crime - or the weak spot in a patient's tumour - to wipe out the problem for good."

The genetic complexity of cancer**, which is flagged by tumour antigens, arises when cancers evolve in a branched manner. The earliest faults are found in all cells, forming the 'trunk' of the disease, while later mutations arise in some cells but not all. It is these 'branches' that allow the disease to adapt and become drug resistant.

Professor Charles Swanton, co-author from the UCL Cancer Institute and a Francis Crick Institute scientist, said: "This is exciting. There was evidence that complex tumours with many mutations could increase the chance of the immune system spotting them; now we can prioritise and target tumour antigens that are present in every cell, the Achilles heel of these highly complex cancers.

"This opens up a way to look at individual patients' tumours and profile all the antigen variations to figure out the best ways for immunotherapy treatments to work, prioritising antigens present in every tumour cell and identifying the body's immune T cells that recognise them. This is really fascinating, and takes personalised medicine to its absolute limit where each patient would have a unique, bespoke treatment."

Dr Quezada added: "For many years we have studied how the immune response to cancer is regulated without a clear understanding of what it is that immune cells recognise on cancerous cells. Based on these new findings, we will be able to tell the immune system how to specifically recognise and attack tumours."

Professor Peter Johnson, Cancer Research UK's chief clinician, said: "This fascinating research gives us vital clues about how to specifically tailor treatment for a patient using their immune system.

"It gets us closer to knowing why some patients respond to immunotherapy treatment and others don't, and how we might select which patients will benefit the most.

"As well as suggesting a new way to treat cancer, the research fills key gaps in our knowledge about the effects of the immune system on tumours. This gives us hope of developing better treatments for some of the cancers we have previously found hardest to treat."

Sam Howard, Chief Executive of Rosetrees Trust, said: "Rosetrees Trust is delighted to be able to support such cutting edge research carried out by outstanding researchers, which potentially has a direct human impact."

This research is published today (Thursday) in Science.
-end-
For media enquiries contact Stephanie McClellan in the Cancer Research UK press office on 020 3469 5314 or, out of hours, on 07050 264 059.

Notes to editor:


* McGranahan et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science

** This phenomenon was first reported by Cancer Research UK scientists in 2012 who were studying kidney cancer. This followed work at The Institute of Cancer Research that had found the same in blood cancers.

Link to animation: https://www.dropbox.com/s/0nbx5amtaban8x4/CRUK_Heterogeneity_final_edit_SOUND_total.mp4?dl=0

About Cancer Research UK
For further information about Cancer Research UK's work or to find out how to support the charity, please call 0300 123 1022 or visit http://www.cancerresearchuk.org. Follow us on Twitter and Facebook.

About Rosetrees Trust

Rosetrees Trust is a substantial family foundation established in 1987 that funds life changing medical research. Rosetrees enables outstanding medical researchers, often at the start of their career, to conduct early stage research. Under the guidance of top researchers, it gives them the opportunity to experiment with ideas and become future leaders in their field. Rosetrees believes that basic (rather than just translational) research is a crucial cog in the scientific wheel and can, ultimately, lead to the major discoveries of our generation. The UK has world class medical research, but lacks funding - especially seed corn funding. Rosetrees aims to change that.

Rosetrees currently supports over 250 live medical research projects, and since establishment over 25 years ago, in excess of £240 million has been invested in world class research, either from Rosetrees, co donations or the major grants that followed from Rosetrees' initial support. Rosetrees has a target of generating £1 billion for medical research.

Rosetrees' unique entrepreneurial philanthropy model sources and selects only the best projects and researchers to support, and then carefully manages the funding throughout the duration. Rosetrees actively seeks trusts and philanthropists to co donate with in order to direct more funds to the best medical research projects, and co donors who fund alongside Rosetrees benefit at no cost from this expertise. http://www.rosetreestrust.co.uk Follow us @RosetreesT

Cancer Research UK

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