A newly discovered gene expression program within neutrophils – a type of immune cell – appears to predict cancer progression across a wide range of tumor types, according to research published this week in . The findings, stemming from work at the Ludwig Institute for Cancer Research in Lausanne, identify a specific marker, CCL3, as a key driver of this process.
Neutrophils are typically known as the body’s first responders to infection, rapidly deploying to sites of injury or invasion. However, their role in cancer has been complex and often contradictory. While they can sometimes help fight tumors, they are also frequently found within the tumor microenvironment, seemingly contributing to cancer growth. This new research sheds light on *how* neutrophils can promote cancer, revealing a specific genetic program that transforms these immune cells into pro-tumor agents.
Researchers found that tumors induce a genetic shift in neutrophils, pushing them towards a state of continuous maturation, ultimately resulting in an “aged” neutrophil characterized by high expression of the chemokine CCL3. These ‘CCL3hi’ neutrophils aren’t simply present within the tumor. they actively adapt to the harsh conditions often found within the tumor microenvironment, particularly areas deprived of oxygen. “We found that tumors induce in neutrophils a genetic program that sets them on a trajectory of continuous maturation, culminating in a terminal ‘aged’ state characterized by high CCL3 expression,” explained Mikaël Pittet, PhD, professor at Ludwig Lausanne and corresponding author of the study.
This adaptation isn’t passive. Once in this aged, CCL3-producing state, the neutrophils activate a suite of genes that directly promote tumor cell survival, and growth. The study, encompassing over 190 tumor samples from both human patients and mouse models, demonstrated the consistency of this pattern across multiple cancer types, including lung and breast cancers. Previous research had already linked neutrophils to the growth of prostate cancer, further supporting these new findings.
CCL3, a chemokine, acts as a signaling molecule, attracting other cells and influencing their behavior. The research suggests that CCL3 produced by these aged neutrophils creates a supportive niche for the tumor, fostering its expansion. The identification of CCL3 and its receptor, CCR1, as key drivers of neutrophil-mediated tumor progression offers a new understanding of how cancers manipulate the immune system to their advantage.
The team developed a sophisticated method for analyzing single-cell RNA sequencing data, allowing them to accurately identify different functional states of neutrophils within tumors. This was crucial, as neutrophils can adopt multiple roles, making it difficult to pinpoint the specific cells driving tumor progression. This new analytical approach allowed researchers to consistently identify this specific population of aged, CCL3-producing neutrophils.
Interestingly, the study also suggests that simply having neutrophils present in the tumor isn’t enough. It’s the specific genetic program and resulting CCL3 production that dictates their pro-tumor activity. Without CCL3, the researchers found, neutrophils lose their ability to promote tumor growth. They retain their normal functions in the bloodstream and can even accumulate within tumors, but no longer contribute to the deleterious reprogramming that fuels cancer progression.
This discovery has significant implications for cancer research and potential treatment strategies. CCL3 could serve as a biomarker to predict which patients are likely to have more aggressive tumors and poorer outcomes. Targeting CCL3 or the signaling pathways it activates could potentially disrupt the pro-tumor activity of neutrophils, offering a new avenue for cancer therapy. The research highlights an “insidious adaptation exploited by cancer cells,” complicating the traditional view of neutrophils solely as anti-pathogen effectors.
While the research provides a significant step forward in understanding the complex interplay between the immune system and cancer, further investigation is needed to fully elucidate the mechanisms involved and to translate these findings into clinical applications. The identification of this conserved genetic program and the role of CCL3 represent a promising new target for future cancer research and treatment development.
