Highlights

In brief

Using advanced genetic analyses in pancreatic tumour models in mice, researchers identified that altered ‘T3’ neutrophils promote tumour growth, leading to a potential strategy for targeting these cells to enhance cancer therapies.

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From immune allies to cancer enemies

12 Aug 2024

Neutrophils, typically our immune defenders, can paradoxically promote cancer progression when altered in tumours.

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).

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References

Ng, M.S.F., Kwok, I., Tan, L., Shi, C., Cerezo-Wallis, D., et al. Deterministic reprogramming of neutrophils within tumors. Science 383 (6679), eadf6493 (2024). | article

About the Researchers

Melissa Ng is currently a Senior Scientist I based at Singapore Immunology Network (SIgN), A*STAR. She received her PhD in Biomedical Sciences from University of California, San Francisco (UCSF) in 2019, where she worked on the development of fetal T cells and their role in immunotolerance in utero under Trevor Burt. Under the mentorship of Lai Guan Ng at SIgN, her postdoctoral work was focused on investigating neutrophil reprogramming in the cancer microenvironment in order to identify potential druggable targets for immunotherapeutic use. Her interest lies in utilising high dimensional techniques in unison with experimental methods to investigate big picture questions in biology.
Immanuel Kwok is a Senior Scientist at A*STAR’s Singapore Immunology Network (SIgN), studying mechanisms of neutrophil activation and reprogramming. He was awarded the Career Development Fund (2021) to discover novel factors for ex vivo expansion of hematopoietic stem cells using spatial technologies. He carried out his PhD studies under the guidance of Lai Guan Ng (SIgN) and I-Hsin Su from Nanyang Technological University, Singapore, studying the ontogeny of neutrophils, which has resulted in numerous high-impact journals including Science, Cell, Immunity and Nature Immunology.
Leonard Tan is a Research Fellow at the Singapore Immunology Network (SIgN). He completed his PhD degree at the National University of Singapore's Yong Loo Lin School of Medicine in 2022. During his PhD studies, he focused on studying the heterogeneity of neutrophils and how they behave in cancer. He specialises in using various imaging techniques like Multiphoton live imaging and 3D optical clearing imaging, as well as working with mouse tumour models. Tan also manages the SIgN Imaging Platform, where he helps other scientists with microscopy and image analysis. One of Tan's significant achievements has been setting up the Spatial Biology & Immune Imaging Centre of Excellence in collaboration with Miltenyi Biotec, which provides advanced imaging services that helps deepen our understanding of the spatial microenvironment of immune responses in diseases.

This article was made for A*STAR Research by Wildtype Media Group