Lionel Apetoh: "We’re gambling on a new immunotherapy route to fight cancer"

It has been barely 10 years since cancer research scientists first began seriously looking at immunity as a potential vector for a cure. While the first immunotherapy treatments are now being used for melanoma, much remains to be discovered and understood in this field. Lionel Apetoh and his team have chosen to focus on the properties of CD4 T lymphocytes in order to develop new treatment options...

Cancer immunology is a relatively recent research field. How did you get involved?

Lionel Apetoh

When I was in high school, I was fascinated by how our immune system works: it was this that encouraged me to study biology. In concrete terms, I was first introduced to immunology when I was on an internship as part of my Master’s degree in Quebec. I then took a pretty conventional path, completing my doctoral thesis in the laboratory led by Laurence Zitvogel, an immunotherapy specialist, followed by a post-doctorate at Harvard University. I got a chance to examine both fundamental questions and those more specifically applied to oncology. At the time, anticancer immunotherapy was still an unknown quantity. Its validity has since been confirmed. Then in 2015, thanks to the European funding I obtained with my lab, we came up with the idea of developing a new immunotherapy route: we are looking at CD4 T lymphocytes, a cell population that’s very important for our usual defense mechanisms.

What makes immunotherapy an original option in the battle against cancer?

The natural course of tumors demonstrates that the immune system is not efficient enough to fight off cancer on its own. To compensate for this, the most logical approach was initially to develop anticancer chemotherapy. A scientific rationale already existed with respect to the immune system’s capacity to fight cancer: in the 1970s, for example, studies had demonstrated that chemotherapy worked less well in mice whose immune defenses had been suppressed. But, while these observations suggested potential cooperation between chemotherapy and immunity, at the time, our knowledge of cellular and molecular biology was inadequate to understand the mechanisms underpinning the success of this combination. Today, we know that there are two different routes: some types of chemotherapy will make it possible to release substances that stimulate the immune system using the destroyed cancer cells. The second route concerns the substances being developed today in the field of immunotherapy: these target key immune system cells, activating them directly and boosting the response against the cancer.

Why are CD4 T lymphocytes the focus of your attention?

These cells work a little like an orchestra conductor: they don’t necessarily have a direct action against tumors but they do release messengers that enable cellular cooperation and hence the destruction of cancer cells. So the idea is to gain a clearer understanding of how this biological cascade operates, with a view to stimulating and developing a new class of immunotherapy treatments. The Starting Grant awarded by the European Research Council (ERC) allows us to focus, in particular, on how the lymphocytes are activated by the surrounding nucleic acids (DNA). In fact, DNA is physiologically present in the nuclei of the body’s cells. If it is abnormally present in another biological compartment, the immune system sends out an alarm signal, to which CD4 lymphocytes respond. And in oncology, some abnormal cells die naturally and chemotherapy accentuates their destruction. Their DNA is therefore released, and potentially identified by the lymphocytes. We therefore started trying to unravel these mechanisms.

The project is a high-risk one, but the potential benefits are also high, something that typically characterizes areas eligible for ERC funding. Quite apart from the sum involved, this grant also gives us five years of latitude, instead of the usual three allowed by most grants. This enables us to work without too much urgency and to explore avenues that we wouldn't otherwise have been able to consider. And we mustn’t forget that the ERC also serves as a quality label, enabling us to attract expert scientists from around the globe...

Find out more about Lionel Apetoh:

Lionel Apetoh is team leader for Regulation of CD4 T cell differentiation by nucleic acids, at the Lipids, Nutrition, Cancer unit (Inserm unit 1231/University of Bourgogne/Agrosup Dijon)