Dying tumour cells alert the immune system to fight cancer.
Cells expressing F-actin (green) and cancer antigen mimic, OVA (pink), which are bound together in the top right panel (merged image). The team showed that the association of mutated cancer antigens with F-actin increases tumour visibility to the immune system. Credit: Jonathan Lim and Oliver Schulz, Nature Immunology.
The immune system provides constant surveillance for the body, aiming to spot and eliminate disease-causing microbes or cancerous cells. But tumour cells develop many features that help them hide from the immune system to avoid being detected and killed.
“It’s like a game of cat and mouse between a tumour and the immune system,” describes Caetano Reis e Sousa, head of the Immunobiology Laboratory at the Crick, who studies how the immune system and cancer interact. “The immune system tries to ‘see’ mutant proteins that give the tumour away, and in turn cancer cells try to lose those mutations, like donning an invisibility cloak.”
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Death of a few cells within tumours is common, for example, following therapy or because a growing cancer outstrips the blood supply. Caetano’s team works on immune cells called dendritic cells that scan the tumour for these dead cancer cells.
“Dendritic cells act like sentinels, sounding the alarm upon spotting dead cancer cells. They then teach other immune cells, particularly T cells, to go off and destroy the remaining living tumour cells that have mutant proteins that give them away, “explains Caetano. “But, until now, we weren’t sure if dendritic cells sorted through cancer cell debris to preferentially instruct T cells to respond to some mutant proteins but not others.”
In a study published today in Nature Immunology, Caetano worked with researchers Jonathan Lim and Oliver Schulz to investigate whether dendritic cells detect dead cancer cells via a receptor called DNGR-1. DNGR-1 detects F-actin proteins, the cell ‘scaffold’ that is exposed when a cancer cell dies.
“We looked at mice with and without the DNGR-1 receptor that were exposed to carcinogens, finding that mice without this crucial receptor developed tumours significantly earlier and to a greater extent,” explains Jonathan, who also works as an oncologist at The Christie hospital. “This mirrors what we see in patients, where high levels of DNGR-1 are associated with better survival.”
Next, the team examined whether certain cancer mutations were more likely to be found in the tumours of mice without DNGR-1. They reported an increase in mutations in proteins that bind to the F-actin scaffold.
“We think that, in mice with DNGR-1, mutations in these proteins are highlighted as a red flag for the immune system,” explains Oliver. “Without DNGR-1, these mutations are less highlighted, so there’s less evolutionary pressure for cancer cells to get rid of them.”
Caetano believes that deploying this knowledge could help make therapies that give the immune system an upper hand. “Now we know that cancer cells are more visible to the immune system if they have mutations in proteins that bind to F-actin, we could work out how to coax the immune system to better detect these mutations,” he says.
Caetano’s team are now exploring whether equipping dendritic cells and other immune cells with better ways to detect F-actin allows the body to recognise cancer cells more easily.
He concludes, “By understanding how tumours are naturally detected by DNGR-1-expressing dendritic cells, we’re hoping to design therapies to boost the immune system’s capability to fight cancer.”
