A new research study led by A*STAR.Singapore Immunology Network (A*STAR.SIgN) has found that neutrophils—one of the most abundant white blood cells in our body—change drastically in certain cancers, adopting a new function whereby they promote tumour growth. By carefully studying neutrophils as soon as they enter the tumour, scientists from A*STAR.SIgN also uncovered ways to accurately differentiate tumour-promoting neutrophils from normal neutrophils present in the rest of the body. Neutrophils play important and irreplaceable roles in fighting infections, hence, depletion of neutrophils due to chemotherapy usually leave cancer patients susceptible to potentially fatal infections.

With the ability to specifically single out tumour-promoting neutrophils, this represents a novel way in which tumours can be targeted while preserving the normal neutrophil response. The study, “Deterministic reprogramming of neutrophils in tumours”, was published in Science.

Neutrophils are characterised as the first responders of the immune system, as they migrate rapidly from the blood into tissues to fight off disease-causing pathogens. In cancer, scientists have previously showed that various types of neutrophils present within the tumour play a crucial role in supporting tumour growth, which in turn lead to poorer clinical outcomes in cancer patients. Yet, it was unclear how these different types of neutrophils were generated, and whether they worked in a co-operative fashion to drive tumour progression. Thus, specific targeting of tumour-promoting neutrophils could not be achieved.

To address this, a team of A*STAR.SIgN scientists utilised an experimental pre-clinical model of pancreatic cancer, demonstrating that diverse types of neutrophils acquired new characteristics and functions once they migrated into the tumour, a process that was termed “reprogramming”. Neutrophils that had undergone this reprogramming process would then be unified as a singular population regardless of their initial starting point. Thus, by tracking the reprogramming process, the team could now study how reprogrammed neutrophils ensured the continued growth of the tumour. Reprogrammed neutrophils promoted the growth of new blood vessels within the centre of the tumour, which likely allowed the tumour to overcome the limited access to oxygen and nutrients. When the researchers specifically blocked this vessel-promoting function of reprogrammed neutrophils, or removed them from interacting with the tumour, they were able to reduce the growth of pancreatic tumours in pre-clinical models.

The team also found similar instances of reprogramming when they re-analysed other published data sets in humans, indicating a common pathway where neutrophils can be similarly modified to promote tumour growth in certain solid cancers. As such, this study holds promise for future therapeutic approaches in cancer that target neutrophil reprogramming and their eventual function, synergising with current treatment and immunotherapies that activate the immune system to destroy tumours.

Dr Melissa Ng, SIgN fellow at A*STAR.SIgN and co-corresponding author on the study, said, “This study leverages the team’s previous work, which identified how diverse neutrophils can be. In this study, we expand on our previous knowledge by uncovering the mechanisms through which tumours induce neutrophils to adopt a tumour-promoting response. This allows us to selectively target reprogrammed neutrophils, which will improve and diversify treatment options for human cancers, while lessening the impact from just targeting neutrophils in a non-specific manner.” 

Prof Lam Kong Peng, Executive Director at A*STAR.SIgN, said, “Breakthrough science, such as this study led by A*STAR.SIgN, is integral as it allows us to build the next generation of cancer immunotherapeutics to improve clinical outcomes for Singapore and Singaporeans.”

The team plans to further investigate the factors that drive neutrophil reprogramming in human cancers. This is crucial for developing more effective ways to target and treat cancer through strategies focused on neutrophils.

Source: Agency for Science, Technology and Research (A*STAR), Singapore