As the immune system's unsung heroes, neutrophils lead fleeting yet vital lives—they last just 12 hours in circulation, but are always ready to spring into action at the first sign of infection or injury. However, their role becomes more sinister when they infiltrate and persist in tumours, often leading to a worse prognosis and reduced survival for cancer patients. This paradoxical behaviour highlights the complex nature of these cells in cancer contexts.
Melissa Ng, a Senior Scientist at A*STAR’s Singapore Immunology Network (SIgN), explained the challenge in understanding these dynamics: “Prior to this study, we did not understand how pro-tumoural neutrophils were generated within the tumour. We knew that an extensive number of tumour neutrophil states were present, but how they related to each other and interacted to drive tumour growth was unknown.”
Ng and SIgN colleagues Immanuel Kwok and Leonard Tan teamed up with local collaborators from A*STAR’s Institute of Molecular and Cell Biology (IMCB) and the National University of Singapore, alongside international partners from China, France, Spain, Italy and Australia. Under the mentorship of Lai Guan Ng, the lead senior author of the study, the team started tracing the transitions neutrophils undergo as they infiltrate tumours, influenced by the surrounding tumour microenvironment.
Using a mouse model with pancreatic tumours, the researchers applied high-dimensional analytical techniques to examine gene expression and epigenetic changes in neutrophils. Ng stated, “We demonstrated that diverse types of neutrophils acquired new characteristics and functions in parallel once they migrated into the tumour—a process called ‘reprogramming’.”
This reprogramming results in what the researchers termed 'T3’ neutrophils, cells marked by a distinct protein, dcTRAIL-R1, which indicates their reprogrammed state. Further analysis of human cancer data showed that these altered neutrophils also appear in solid tumours. The specific pattern of genes activated in T3 neutrophils acts like a fingerprint, helping predict poorer survival rates in various cancers.
Further investigations by the team showed that only when reprogrammed neutrophils and tumour cells are introduced together into mice, tumour growth and angiogenesis (blood vessel growth) are enhanced, indicating that T3 neutrophils drive cancer progression. The research then pivoted to targeting these harmful cells; by neutralising T3 neutrophils or their activity with antibodies against dcTRAIL-R1 or VEGFA, a key protein in angiogenesis, the team successfully reduced tumour sizes.
“Our work demonstrated that tumour-reprogrammed neutrophils can be specifically targeted,” explained Ng. “Thus, we can develop strategies that synergise with current immunotherapies while sparing normal neutrophils.”
Moving forward, the team is continuing their work together on unravelling the factors behind neutrophil reprogramming to develop advanced neutrophil-targeting strategies for treating cancer. This ongoing research not only helps demystify the complex roles of neutrophils in cancer but also presents hopeful avenues for therapeutic intervention.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN) and the Institute of Molecular and Cell Biology (IMCB).
