Reprogrammed neutrophils promote tumor growth

Predicting tumor progression is one of the major challenges in oncology. Scientists at the University of Geneva (UNIGE) and the Ludwig Institute for Cancer Research have discovered that neutrophils, a type of immune cell, undergo reprogramming when they come into contact with the tumor ecosystem and contribute to its progression. They then produce a molecule - the chemokine CCL3 - which promotes cancer growth rather than fighting it. This mechanism appears to be a major variable in tumor biology and could serve as an indicator of disease progression. These findings are published in the journal Cancer Cell.

A tumor is not just a cluster of cancer cells but develops within a complex ecosystem where different cell populations interact. "One of the difficulties lies in identifying, in an environment we are only now beginning to understand, the elements that truly influence the tumor's ability to grow," explains Mikaël Pittet, full professor in the Department of Pathology and Immunology and at the Translational Research Centre in Onco-Haematology (CRTOH) at the UNIGE Faculty of Medicine, and member of the Lausanne Branch of the Ludwig Institute for Cancer Research, who led this work.

"In 2023, we showed that the expression of two genes in macrophages is strongly linked to disease progression. This constitutes a simple but informative variable for understanding tumors and anticipating their trajectory. Our new study highlights a second variable, this time involving another population of immune cells: neutrophils."

A deleterious reprogramming

Neutrophils represent one of the most abundant populations in the immune system. They typically constitute the first line of defence against infections and injuries. In the context of cancer, however, their presence is generally a bad omen. "We discovered that neutrophils recruited by the tumor undergo a reprogramming of their activity: they begin producing a molecule locally-the chemokine CCL3-which promotes tumor growth," explains Mikaël Pittet.

An experimental and bioinformatics challenge

"Neutrophils are particularly difficult to study and to manipulate genetically," explains Evangelia Bolli, co-lead author of the study and responsible for its experimental component, then a postdoctoral researcher in the Department of Pathology and Immunology at the UNIGE Faculty of Medicine, now a postdoctoral researcher at the Broad Institute of MIT and Harvard. "We combined different approaches to control the expression of the CCL3 gene specifically in neutrophils, without inhibiting it in other cells. A delicate exercise!" The result? Without CCL3, neutrophils lose their pro-tumor action. They retain their physiological functions in the blood and can even accumulate in tumors, but no longer adopt the deleterious reprogramming previously observed.

To complete their analysis, the research team re-examined data from numerous independent studies. "We had to innovate to detect neutrophils more accurately," explains Pratyaksha Wirapati, co-first author and bioinformatics specialist. "Their low genetic activity often makes them invisible using standard analysis tools. By developing a new method, we have been able to show that, in many cancers, these cells share a common trajectory: they produce large amounts of CCL3, which is associated with pro-tumor activity."

Towards a potential prognostic marker

With CCL3, Mikaël Pittet's team has now identified a new variable likely to provide information on tumor progression. "We are deciphering the 'identity card' of tumors, by identifying, one by one, the key variables that determine the evolution of the disease," explains the researcher. "Our work suggests that there is a limited number of these variables. Once they are properly identified, they could help better tailor the management of each patient and, ultimately, offer more effective and personalized care."