Cell toxicity during immunotherapy is a major limitation to cancer treatment, but researchers are now able to isolate harmful cell reactions with a renewed potential to offer treatment without side effects.

Immunotherapy. Image Credit: Lightspring/Shutterstock.com

Despite immunotherapy rapidly advancing the field of cancer treatment, inflammatory reactions in healthy tissues frequently trigger side effects that lead to the permanent discontinuation of treatment. Indeed, the treatment is based on massive stimulation of the immune system but does not proceed without consequences as cell populations suffer from toxic effects.

This induced toxicity remains poorly understood, but scientists from the University of Geneva (UNIGE), Switzerland, and Harvard Medical School, United States, have succeeded in establishing a breakthrough to distinguish deleterious from beneficial cells produced during the immune reaction.

"When the immune system is activated so intensively, the resulting inflammatory reaction can have harmful effects and sometimes cause significant damage to healthy tissue", stated Mikal Pittet, holder of the ISREC Foundation Chair in Onco-Immunology at UNIGE Faculty of Medicine Department of Pathology and Immunology and Centre for Translational Research in Onco-Haematology.

Therefore, we wanted to know if there are differences between a desired immune response, which aims to eliminate cancer, and an unwanted response, which can affect healthy tissue. The identification of distinctive elements between these two immune reactions would indeed allow the development of new, more effective and less toxic therapeutic approaches."

The study, published in the journal Science Immunology, showed that cell populations could be distinguished based on whether they were deleterious immune reactions or those targeting tumor cells that are sought after. Such findings may provide more accurate and more effective treatments whilst minimizing the harmful by-products incurred during immunotherapy.

Researchers used samples from liver biopsies from patients who had suffered such toxic reactions to study the cellular and molecular mechanisms causing such reactions.

During immunotherapy, macrophage and neutrophil populations appear to be the two main cell types responsible for attacking healthy tissue but are not involved in killing targeted cancer cells. Dendritic cells are also not involved in attacking healthy tissue but are essential cell types for eliminating cancer cells.

"Immunotherapies can trigger the production of specialized proteins that alert the immune system and trigger an inflammatory response, explains Mikal Pittet. In a tumor, these proteins are welcome because they allow the immune system to destroy cancerous cells. In healthy tissue, however, the presence of these same proteins can lead to the destruction of healthy cells. The fact that these inflammatory proteins are produced by such different cells in tumors and healthy tissue is, therefore, an interesting finding."

However, the cell types involved differ in density as dendritic cells are very rare whereas macrophages and neutrophils are much more common, this is a key indication as to which cells may be responsible for unwanted cell damage. Importantly, some macrophages contained within organs do not necessarily inhibit inflammation but, when stimulated by immunotherapies they trigger a harmful inflammatory response in the healthy tissue where they reside, thus explaining why toxicity can affect different organs.

The production of inflammatory proteins by macrophages when activated by drugs then activates neutrophils in turn, which execute the harmful toxic reaction. This chain of reaction is a key process to the inflammatory response and induced cell toxicity observed in immunotherapy.

Mikal Pittet suggests "This opens the possibility of limiting immunotherapy's side effects by manipulating neutrophils".

By testing this loophole in mice, the researchers were able to short-circuit this process using inhibitors that negate the action of factors produced by neutrophils. These inhibitors are already being used to modulate the immune response in people with arthritis and could perhaps be useful in inhibiting the toxic effects of neutrophils during immunotherapy.

Furthermore, inhibiting neutrophils could be a more effective way to fight cancer: in addition to triggering a toxic response, some of these cells also promote tumor growth. Thus, by managing to control them, we could have a double beneficial effect: overcome the toxicity in healthy tissues, and limit the growth of cancerous cells"

Mikal Pittet

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