Immunotherapy is gaining ground on ‘classic’ cancer therapies. While approaches are still limited, the team of Prof. Sophie Lucas has made a discovery, published in the journal PNAS, that could help strengthen immune responses against tumours and support development of a new cancer immunotherapy strategy.
So-called ‘classic’ cancer treatment therapies directly attack cancer cells with the aim of destroying them. Chemotherapy, radiotherapy and surgery have existed for a long time and often entail severe side effects because while they target proliferating cancer cells they also affect some normal cells. Cancer type determines the treatment or combination of treatments.
Over the past decade, an alternative has been in development: immunotherapy. Rather than attack tumours, it helps strengthen the immune system in order to counter cancer cells. It’s a less invasive therapy that aims to boost immune system cells in order to incite the system to reject cancer. While the idea is promising, numerous factors come into play. Currently, immunotherapy is effective only among a minority of patients and in certain cases.
‘The problem is that the tumour paralyses the immune system’, says Sophie Lucas, a research group director at the de Duve Institute. ‘When a patient can develop immune cells, such as T lymphocites, that recognise cancer cells, we know the cancer can be eliminated. But the cancer often advances anyway because the anti-tumour T lymphocytes are inhibited. Some very effective immune approaches already exist that allow for blocking the inhibiting receptors on the surface of anti-tumour T lymphocytes. This blockage allows the immune system to be reactivated. Our work aims to revive immune responses against the tumour. Our laboratory focuses on an immune system inhibition mechanism that current therapies don’t target.’ A recent discovery, published in the journal PNAS, could serve as a new approach to cancer immunotherapy.
Understanding how Tregs work
In concrete terms, at the de Duve Institute Prof. Lucas’s team studies regulatory T lymphocytes (Tregs) to understand how they suppress immune cells. In plain language, the immune system sometimes destroys healthy tissue. To avoid this, several control mechanisms exist, including Tregs, blood cells specialised in immunosuppression, which protects us against auto-immune diseases by preventing inappropriate immune responses.
Two types of Treg dysfunction exist. When their immunosuppressive functions are diminished, an auto-immune disease (such as type 1 diabetes or multiple sclerosis) can be triggered. Conversely, Tregs can work excessively and thus prove harmful by blocking immune responses that are not auto-immune and are even desirable. They thus contribute to the development of diseases, such as cancer, that could be controlled by efficient immune responses. Among cancer patients, they help tumours grow by suppressing immune responses against cancer cells – the Tregs are counterproductive.
This is what Prof. Lucas’s team studies. She is trying to identify the mechanisms by which Tregs suppress immune responses. The long-term objective is to develop new therapeutic strategies that modify Treg activity in patients suffering from cancer or auto-immune diseases.
By carrying out this work, Prof. Lucas and her fellow researchers Amandine Collignon, Stéphanie Liénart and Julie Stockis made a discovery, published in the journal PNAS in November 2017. The article is based on the supposition that antibodies, specifically the anti-β8 antibodies that block the immunosuppressive function of Tregs, could revive anti-tumour immune responses.
Blocking Treg immunosuppression with antibodies
Working in the laboratory, the researchers first discovered that Tregs produce a cytokine called TGF-β. It’s a molecule with very powerful immunosuppressive properties, which sends a suppression message and blocks other immune cells. Two years ago, their work made it possible to determine that this TGF-β was produced on the surface of Tregs from a protein called GARP.
‘But GARP isn’t enough’, explains Prof. Sophie Lucas. ‘We discovered that another protein was essential for the liberation of TGF-β by Tregs. This other protein is known by the name integrin αVβ8. Here in the laboratory, we were able to show that using anti-integrin monoclonal antibodies allows for blocking the production of TGF-β, and thus immunosuppression by Tregs. By preventing their immunosuppressive function, we could revive anti-tumour immune responses. This is very important: we remove a constraint on the immune system. This discovery could lead to the development of an additional weapon in the arsenal of immunotherapy methods, which is currently not very large.’
Possibility of a new therapeutic approach
It’s essential to develop new approaches because immunotherapy works for only a minority of patients. Current available molecules act on only certain types of cancer, with no guarantee of results. ‘We can combine this discovery, once it’s developed, with other forms of immunotherapy, or even with chemo or radiotherapy, to improve the effectiveness or diminish toxicity’, Prof. Lucas explains. ‘Overall, we’re making progress in the field: certain immunotherapies are covered by insurance as treatment. They’re administered to patients who already tried traditional treatments. On the experimental level, the idea is to consider them as first-line therapies so they’re administered sooner and combined with other forms of therapy. Many clinical trials are underway.’
At this stage, the latest laboratory discoveries are more experimental because they aim at new targets. Work on the GARP protein is at the stage of preclinical testing, on mice. ‘We envision clinical treatments, but they won’t be tested on humans for another year or two. For the last discovery, concerning integrin αVβ8, we don’t have a plan yet. We’re continuing to explore the biology of integrin and decrypt the molecular mechanism. We’re at the proof of concept stage.’
This continuing research is financed by FNRS, WELBIO and the European Research Council, and conducted in collaboration with the University of California, San Francisco.
Anne-Catherine De Bast
A glance at Sophie Lucas'Bio
Sophie Lucas graduated from UCL in 1994 with a PhD in medicine, then earned a PhD in biomedical sciences in 2000 for her work in tumour immunology, carried out in the laboratory of Professor Thierry Boon at the Ludwig Institute for Cancer Research. She then completed a two-year postdoctoral fellowship at the Genentech biotechnology company in San Francisco, where she studied new cytokines and their receptors in Frédéric de Sauvage’s laboratory. In 2004, she founded her own research group at the de Duve Institute, on the campus of the Faculty of Medicine at UCL. A qualified researcher at the FNRS since 2008, she became a professor in Cancer Immunotherapy at UCL in October 2016. Her research focuses on the role of regulatory T lymphocytes in suppressing immune responses in humans, and more particularly in patients suffering from cancer.