By identifying the toxicity mechanism induced by immunotherapy, scientists at UNIGE and Harvard Medical School are paving the way for cancer treatments with fewer side effects
In recent years, immunotherapy has revolutionized cancer therapy. However, inflammatory reactions in healthy tissue often trigger side effects that can be serious and lead to permanent discontinuation of treatment. This toxicity is still poorly understood and represents a major obstacle to the application of immunotherapy. Scientists at the University of Geneva (UNIGE), Switzerland, and the Harvard Medical School, USA, have succeeded in understanding the differences between harmful immune responses and those that target the targeted tumor cells to determine. It appears that while the immune mechanisms are similar, the cell populations involved are different. This work published in the journal Science immunology, enables more targeted, effective and less dangerous treatments for cancer patients.
Based on massive stimulation of the patient’s immune system, immunotherapies have saved many lives. Unfortunately, they are not without consequences. “When the immune system is activated so intensely, the resulting inflammatory reaction can have harmful effects and sometimes significantly damage healthy tissue,” says Mikaël Pittet, holder of the ISREC endowed chair for onco-immunology at the Department of Pathology of the Medical Faculty of UNIGE and Immunology and Center for Translational Research in Onco-Hematology and member of the Swiss Cancer Center Leman. “That’s why we wanted to know whether there are differences between a desired immune response that aims to eradicate cancer and an undesirable response that can attack healthy tissue. The identification of characteristic elements between these two immune responses would indeed enable the development of new, more effective and less toxic therapeutic approaches. “
Using liver biopsies from patients treated at CHUV and HUG who had suffered such toxic reactions, the scientists examined the cellular and molecular mechanisms to uncover similarities and differences.
A similar reaction, but with different cells
In an immunotherapy-induced toxic response, two types of immune cells – macrophage and neutrophil populations – appear to be responsible for attacking healthy tissue, but are not involved in killing cancer cells. In contrast, another cell type – a population of dendritic cells – is not involved in attacking healthy tissue, but is essential for the elimination of cancer cells. “Immunotherapies can trigger the production of specialized proteins that alert the immune system and trigger an inflammatory response,” explains Mikaël Pittet. These proteins are welcome in a tumor because they enable the immune system to destroy cancer cells. However, in healthy tissue, the presence of these proteins can lead to the destruction of healthy cells. It is therefore an interesting finding that these inflammatory proteins are produced by such different cells in tumors and healthy tissue. “
Dendritic cells are very rare, while macrophages and neutrophils are much more common. Some macrophages are present in most of our organs from the embryonic stages of development and remain there throughout our lives. Contrary to what was previously assumed, these macrophages do not necessarily inhibit inflammation, but can, stimulated by immunotherapy, trigger a harmful inflammatory reaction in the healthy tissue in which they are located and thus explain why toxicity can affect various organs.
Neutrophil neutralization for a double benefit
When macrophages are activated by drugs, they produce inflammatory proteins. These in turn activate neutrophils, which carry out the toxic reaction. “This opens up the possibility of limiting the side effects of immunotherapy by manipulating neutrophils,” says Mikaël Pittet.
The research team confirmed their discovery by studying the immune responses of mice whose cell activity was modulated with genetic tools. They were able to identify a loophole that could be exploited to eliminate these side effects. In fact, neutrophils produce several factors that are important in the development of toxicity, including TNF-α, which could be a therapeutic target. TNF-α inhibitors are already used to modulate the immune response in people with arthritis and could potentially be useful in the cancer setting to inhibit the toxic effects of neutrophils during immunotherapy. “In addition, the inhibition of neutrophils could be a more effective way to fight cancer: some of these cells not only trigger a toxic reaction, but also promote tumor growth. So if we manage to control them, we could have a double positive effect: overcoming toxicity in healthy tissue and limiting the growth of cancer cells, ”concludes Mikaël Pittet.
The Swiss Cancer Center Léman is a network that unites the universities of Geneva (UNIGE) and Lausanne (UNIL), EPFL, HUG and CHUV under one roof. This alliance unites all specialists in the chain from the laboratory to the hospital bed under a federal and regional identity.