Cancer’s ability to evolve and resist treatment is a central challenge in oncology. Now, researchers are uncovering a surprising way tumors may be hijacking the body’s own immune defenses, turning cells meant to fight cancer into allies that actively promote its growth. A study published , in the journal Cancer Cell, details how tumors can reprogram neutrophils – a common type of immune cell – to produce a molecule called CCL3, which fuels tumor progression.
How Immune Cells Can Be Subverted
Neutrophils are typically among the first responders to infection, acting as a crucial part of the body’s initial defense. However, their presence within a tumor environment often correlates with a poorer prognosis. Scientists at the University of Geneva (UNIGE), working with the Ludwig Institute for Cancer Research, have discovered that tumors don’t just passively attract neutrophils; they actively alter their behavior.
“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, 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.
This shift transforms a protective immune response into one that inadvertently supports cancer’s survival and spread. The research suggests that CCL3 production by these altered neutrophils is a consistent pattern across many different cancer types, potentially serving as a valuable signal for tracking disease progression.
Overcoming Technical Challenges to Understand Neutrophil Behavior
Studying neutrophils presents significant 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 now a postdoctoral researcher at the Broad Institute of MIT and Harvard.
To overcome these challenges, the research team employed a series of sophisticated experimental strategies designed to precisely control the CCL3 gene within neutrophils without affecting other cell types. “We combined different approaches to control the expression of the CCL3 gene specifically in neutrophils, without inhibiting it in other cells. A delicate exercise!” Bolli notes.
When CCL3 production was blocked, the researchers observed a significant change: neutrophils no longer supported tumor growth. Importantly, the neutrophils remained functional in the bloodstream and continued to accumulate within the tumors, but the harmful reprogramming process was halted.
Confirming a Common Pattern Across Cancer Types
The findings were further strengthened through a comprehensive reanalysis of data from numerous independent studies. This required the development of new analytical methods to accurately detect neutrophils, which can often be “invisible” using standard tools due to their low genetic activity.
“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 Potential Biomarker for Tumor Progression
The identification of CCL3 as a key driver of neutrophil-mediated tumor growth offers a promising new avenue for understanding cancer evolution. Researchers believe that identifying key variables like CCL3 could lead to more tailored and effective cancer treatments.
“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, offer more effective and personalized care.”
This research builds upon previous work by the same team, who in 2023 identified two genes in macrophages that are strongly linked to disease progression. The identification of CCL3 in neutrophils adds another crucial piece to the puzzle of understanding the complex interplay between the immune system and cancer.
The findings highlight the importance of considering the tumor microenvironment – the complex ecosystem surrounding a tumor – when developing cancer therapies. Targeting the interactions between tumors and immune cells, such as neutrophils, may offer new strategies for improving treatment outcomes.
