Dr Rahul Roychoudhuri at the Babraham Institute discusses awakening the immune system to defeat cancer
Like an army on guard, our immune system is fighting off new threats to us daily. So how is cancer able to develop? And how can we use the body's own defences to defeat it?
For decades, doctors and scientists have fought cancer by targeting tumours.
Chemotherapy, radiotherapy, drugs and surgery have been the established weapons against the leading cause of premature death in the UK.
But in recent years, another method has been deployed: targeting the body’s own immune system.
Immunotherapy has emerged as a hugely promising and powerful tool – substantially extending the lives of patients for whom other treatments were no longer effective or possible.
At the Babraham Institute, Dr Rahul Roychoudhuri is exploring some of the mechanisms behind how our immune system decides whether what it encounters is friend or foe. It is a process critically important in preventing autoimmunity, where the body attacks itself, and guiding immune responses against infections and cancer.
“Peculiarly, it’s a decision which the immune system finds particularly hard to make in cancer,” says Dr Roychoudhuri.
“The textbook understanding of immunology for the last few decades has been that the immune system is like a standing army waiting for a potential array of foreign invaders.”
It was thought that any such soldiers – white blood cells known as T cells – that would have been “self-reactive” and attacked the body were simply destroyed as they were generated in the thymus, leaving us with a healthy repertoire of troops ready to fight marauding diseases.
But the truth is more complex.
“It has turned out that a number of mechanisms exist both within and without that standing army of soldiers to prevent excessive immune responses,” said Dr Roychoudhuri. “For example, a specialised subset of T cells, called regulatory T cells suppress the other T cells, called effector T cells, and are required to prevent otherwise lethal inflammation.
“So it’s not just a standing army. There are military police that are constantly acting to stop the other soldiers, the effector T cells, from brawling.
“It turns out that these military police, or regulatory T cells, have a significant veto power over almost every immune reaction that happens in the body, and especially those that happen in cancer.”
Dr Roychoudhuri and his team are interested in the mechanisms that control regulatory T cell responses – and how they might be manipulated to tackle disease.
“Three or four decades ago, a majority of immunologists and cancer biologists thought the immune system had very little to do with cancer,” he says.
“This opinion was, in part, fuelled by the observation that tumours grew fairly similarly in normal mice and mice completely deficient of the adaptive immune system.
“But that result is better understood in the context of the immune system having activating components and suppressive components.”
Cancers co-opt regulatory T cells to prevent effector T cells from doing their job.
“The immune system is confused in cancer. It’s a bit like a bunch of squabbling painter-decorators who can’t decide what colour to paint your wall and you arrive at the end of the day and they haven’t done anything,” explains Dr Roychoudhuri.
“The suppressive factors play a powerful role in cancer and prevent the adaptive immune system doing anything about it.
“So one way we are looking to exploit the knowledge we’re gaining is to try manipulate immune function in cancer.
“In part, similar mechanisms that prevent you from having an autoimmune or allergic immune response – for example, every time you eat a sandwich – prevent successful immune responses in tumours.
“What the tumour tries to do is co-opt or hijack mechanisms normally present to protect you from autoimmunity and allergy.
“In work undertaken by Dr Teresa Lozano in the lab, we are collaborating with a company called Cancer Research Technology to develop new drugs that will stimulate immune activation in cancer. This work is supported by Cancer Research UK. Hopefully these drugs will work by preventing the function of regulatory T-cells within tumours.”
In other words, blocking the military police will allow the immune system troops to evict the enemy.
Interactions between the many pharmaceutical companies on the Babraham Research Campus and scientists at the Babraham Institute, which is funded by the Biotechnology and Biological Sciences Research Council (BBSRC), are common.
“The Babraham Research Campus is a melting pot for industrial-academic collaboration. It’s really exciting for us scientists at the Babraham Institute to see the basic research findings we make in the laboratory used as a basis for the development of new therapies,” says Dr Roychoudhuri.
But there’s a challenge for the researchers.
Regulatory T cells are there for a reason – and if you stop them completely, you may unleash the potential for destructive immune responses against yourself and innocuous foreign substances.
“That’s very possible,” says Dr Roychoudhuri. “One of the toxic side effects of immunotherapy is that we may unleash immune activation at non-tumour sites.
“So one project a doctoral researcher in the lab, Francis Grant, is undertaking, is trying to understand whether there is a particular characteristic of regulatory T cells within tumours that may enable their selective targeting.
“That’s another area on which we are collaborating with Cancer Research Technology on the Babraham Research Campus.”
Awakening powerful immune responses against cancer safely is now the aim of researchers, who also want to learn more about why it is not effective in all patients.
Although there are potential side effects, such therapies are already having life-changing impacts for some individuals with cancer.
“Immunotherapy is revolutionising the cancer treatment landscape in general,” says Dr Roychoudhuri.
“For many decades pre-clinical research has focused on the molecular mechanisms that drive cancer from within. However, tumour cells are genetically unstable. Cancer is a Darwinian mass: it is constantly evolving to escape selective pressure provided by drugs.
“But the immune system is encoded by the host and does not change when you use drugs to stimulate it.”
A major paradigm shift in cancer treatment came in 2014, when antibodies that unleash the activity of effector T cells – known as ‘immune checkpoint inhibitors’ – were approved for use on skin cancer patients in the US.
Since then, immune checkpoint inhibitor therapies targeting both CTLA-4 and PD-1 pathways have either been approved for use or are undergoing clinical trials for use in malignant melanoma, non-small-cell lung cancer, renal-cell cancer, bladder cancer, head and neck cancer, ovarian and brain cancer in the UK.
What is particularly exciting is that these therapies can work for patients whose cancer who has metastasised – meaning other, secondary tumours have grown.
“It is starting to make a real difference to the lives of patients with metastatic cancer,” says Dr Roychoudhuri.
Among the pioneers of the field of immunotherapy was Dr Steven Rosenberg at the National Cancer Institute in the US, where Dr Roychoudhuri worked as a postdoctoral scientist in the laboratory of Dr Nicholas Restifo.
Dr Roychoudhuri predicts that in the coming years we will learn more about how to ensure the immune response targets tumours, rather than causing issues elsewhere in the body.
“That will need a careful understanding of the specific nature of tumour immune systems,” he says.
“We are getting there with high-resolution cellular and molecular analyses of the immune system within tumours and comparing it to those within other tissues.”
His work – aided by the £200,000 research prize from the Lister Institute – will help to understand how T cells make the critical decision of whether to become an effector or regulatory T cell with implications for understanding how immune function is suppressed within tumours.
Honoured by £200,000 prize
Dr Rahul Roychoudhuri said he was honoured to be awarded a £200,000 prize designed to support outstanding young independent researchers making a real difference to biomedical research.
The group leader at Babraham, who works with two post-docs and two PhD students, was selected to receive the Lister Institute Research Prize Fellowship to support him in using powerful new genetic screening approaches to identify the functions of key genes and understand immune system functions.
Dr Roychoudhuri said: “It’s an honour to be recognised by the Lister Institute and to join such a respected fellowship. I look forward to getting started on the new research this award will help to support and I hope that what we learn will change our understanding of the immune system.”
The director of the Babraham Institute, Professor Michael Wakelam, said: “Rahul is a rising star in his field and I’m thrilled that the quality of his work has been recognised by the Lister Institute.
“The Lister Prize can be a real boost to the career of outstanding young scientists and I am confident that Rahul will make the most of this opportunity.”
Dr Roychoudhuri studied clinical medicine and natural sciences at the University of Cambridge and King’s College London.
He gained his PhD working with Dr Gary Nabel at the US National Institute of Allergy and Infectious Diseases (NIAID) and completed postdoctoral research with Dr Nicholas Restifo at the US National Cancer Institute.
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