When immune cells stop fighting cancer and start helping it

Once exposed to the tumor ecosystem, these immune cells begin producing a molecule known as the chemokine CCL3. Rather than helping the body fight disease, CCL3 encourages tumors to grow. Because this process appears across many cancer types, it may serve as a useful signal for tracking disease progression. The findings were published in the journal Cancer Cell.

Tumors Grow Within a Complex Cellular Environment

Cancer does not develop in isolation. Tumors exist within a highly interactive environment made up of many different cell types, all influencing one another. Identifying which of these interactions truly drive tumor growth is a major challenge.

“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.

Pittet notes that this study builds on earlier findings. “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.”

When Neutrophils Switch From Defenders to Tumor Promoters

Neutrophils are among the most abundant immune cells in the body and usually serve as an early line of defense against infection and injury. In cancer, however, their presence often signals a worse outcome.

Researchers found that tumors actively recruit neutrophils and alter how they behave. “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.

This shift turns a normally protective immune response into one that helps cancer thrive.

Overcoming Technical Barriers to Study Neutrophils

Studying neutrophils presents major technical hurdles, particularly when it comes to genetic manipulation. “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.

To overcome this challenge, the team used multiple experimental strategies to precisely control the CCL3 gene in neutrophils without affecting other cells. “We combined different approaches to control the expression of the CCL3 gene specifically in neutrophils, without inhibiting it in other cells. A delicate exercise!” she says.

When CCL3 was removed, neutrophils no longer supported tumor growth. They continued to function normally in the bloodstream and were still able to accumulate inside tumors, but the harmful reprogramming no longer occurred.

Large Data Analysis Confirms a Common Pattern

The researchers strengthened their findings by reanalyzing data from many independent studies. Detecting neutrophils in these datasets required new analytical methods.

“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.”

CCL3 as a Possible Marker of Tumor Progression

By identifying CCL3 as a key driver of neutrophil-driven tumor growth, the research team has uncovered a promising new variable for understanding how cancers evolve.

“We are deciphering the ‘identity card’ of tumors, by identifying, one by one, the key variables that determine the evolution of the disease,” explains Pittet. “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.”