Scientists at the Garvan Institute of Medical Research have captured, for the first time, 'housekeeping' immune cells actively attacking and engulfing live melanoma cells – a discovery that could change the way we approach treatment for one of Australia's most common and deadly cancers.
The findings, published today in the Journal of Experimental Medicine , reveal a previously overlooked population of immune cells called macrophages that patrol the edges of melanoma tumours, steadily engulfing cancer cells and slowing tumour growth.
"This is the first time anyone has captured a macrophage attacking and engulfing a live cancer cell in real time," says Dr Yuki Keith, first author of the research. "We always suspected macrophages were doing more than we gave them credit for – now we have the video footage to prove it. Studying this in a living system is crucial because it is more representative of what happens in real life, showing the complexity of the immune system and paving the way for the treatments of the future."
A hidden army in the skin
Macrophages are a type of immune cell that makes up as much as 30 per cent of the cells within a melanoma tumour. While they have long been known to play a role in cancer, there has been little clarity around whether they help or hinder tumour growth.
In the past, researchers have tried indiscriminately eliminating all the macrophages in the body to see how it affects the tumour.
However, Dr Keith's team found that not all macrophages in the skin were the same, identifying one particular subpopulation that expressed a protein called CD169. By specifically targeting and depleting these CD169-positive macrophages, they found the tumours grew larger. This shows that these specific macrophages were preventing the melanoma from growing.
Watching cancer cells being eaten in real time
The team used intravital two-photon microscopy – an advanced imaging technique that allows them to watch biological processes unfold at the cellular level inside living organisms. In mice, the researchers observed the CD169-positive macrophages physically engulfing live melanoma cells. To confirm the clinical relevance of their real-time footage, collaborators at Melanoma Institute Australia analysed human tissue, finding these same macrophages present in healthy human skin and enriched around the margins of human melanoma tumours.
"Macrophages have always been known as the body's housekeepers – they clear away dead cells and debris," explains Professor Tri Phan, senior author on the paper. "What Dr Keith caught on camera was these cells actively nibbling away and engulfing live cancer cells, constraining tumour growth. Critically, this attack appears to occur independently of T cells and B cells – the immune players most commonly credited with fighting cancer – which made the discovery unexpected, and genuinely exciting."
Implications for immunotherapy
This independent first strike has big implications for immunotherapy. Immune checkpoint blockade therapy, which relies on T cells to seek out and destroy cancer cells, has transformed the treatment of advanced melanoma – but currently only around half of patients respond, necessitating more effective treatments. A major hurdle is the so-called immune 'cold tumour' – a tumour that completely locks out T cells.
"While macrophages are known as the body's housekeepers, they also have a second job: acting as immune informants," Dr Keith explains. "Once they consume a threat, they chew it up and display a piece of it on their surface, like a biological 'red flag'. We suspect that these CD169-positive macrophages are doing exactly this with the live cancer cells, which means they could hold the key to calling the T cell cavalry into the tumour to finish the job."
The team's next step is to understand exactly how these CD169-positive macrophages communicate with T cells.
"If we can harness this population of macrophages, we potentially have an immune army already in place, ready to be mobilised," says Professor Phan. "Future treatments could involve developing targeted drugs that boost their numbers, or make them 'hungrier' or better at tagging cancer cells for killing. By combining this approach with existing therapies, we could potentially make immunotherapy work for a much larger group of patients. This could also apply to many cancers beyond melanoma, as macrophages are highly abundant in most solid tumours."
