The immune system automatically destroys dysfunctional cells such as cancer cells, but cancerous tumours often survive nonetheless.

A new study by Salk scientists shows one method by which fast-growing tumours evade anti-tumour immunity.

The Salk team uncovered two gene-regulating molecules that alter cell signalling within tumour cells to survive and subvert the body's normal immune response, reported in Nature Cell Biology.

The discovery could one day point to a new target for cancer treatment in various types of cancer.

"The immunological pressure occurring during tumour progression might be harmful for the tumour to prosper," says Salk Professor Juan Carlos Izpisua Belmonte, senior author of the work and holder of the Roger Guillemin Chair. "However, the cancer cells find a way to evade such a condition by restraining the anti-tumour immune response."

Cancerous tumours often grow so fast that they use up their available blood supply, creating a low-oxygen environment called hypoxia.

Cells normally start to self-destruct under hypoxia, but in some tumours, the microenvironment surrounding hypoxic tumour tissue has been found to help shield the tumour.

"Our findings actually indicate how cancer cells respond to a changing microenvironment and suppress anti-tumour immunity through intrinsic signalling," says Izpisua Belmonte. The answer was through microRNAs.

MicroRNAs--small, noncoding RNA molecules that regulate genes by silencing RNA--have increasingly been implicated in tumour survival and progression.

To better understand the connection between microRNAs and tumour survival, the researchers screened different tumour types for altered levels of microRNAs.

They identified two microRNAs--miR25 and miR93-- whose levels increased in hypoxic tumours.

The team then measured levels of those two microRNAs in the tumours of 148 cancer patients and found that tumours with high levels of miR25 and miR93 led to a worse prognosis in patients compared to tumours with lower levels.

The reverse was true for another molecule called cGAS: the lower the level of cGAS in a tumour, the worse the prognosis for the patient.

Previous research has shown that cGAS acts as an alarm for the immune system by detecting mitochondrial DNA floating around the cell--a sign of tissue damage--and activating the body's immune response.

"Given these results, we wondered if these two microRNA molecules, miR25 and miR93, could be lowering cGAS levels to create a protective immunity shield for the tumour," says Min-Zu (Michael) Wu, first author of the paper and a research associate in Salk's Gene Expression Laboratory.

That is exactly what the team confirmed with further experiments.

Using mouse models and tissue samples, the researchers found that a low-oxygen (hypoxia) state triggered miR25 and miR93 to set off a chain of cell signalling that ultimately lowered cGAS levels.

If the researchers inhibited miR25 and miR93 in tumour cells, then cGAS levels remained high in low-oxygen (hypoxic) tumours.

Researchers could slow tumour growth in mice if they inhibited miR25 and miR93.

Yet, in immune-deficient mice, the effect of inhibiting miR25 and miR93 was diminished, further indicating that miR25 and miR93 help promote tumour growth by influencing the immune system.

Identifying miR25 and miR93 may help researchers pinpoint a good target to try to boost cGAS levels and block tumour evasion of the immune response.

However, the team says directly targeting microRNA in treatment can be tricky.

Targeting the intermediate players in the signalling between the two microRNAs and cGAS may be easier.

"To follow up this study, we're now investigating the different immune cells that can contribute to cancer anti-tumour immunity," adds Wu.

Source: Salk Institute for Biological Studies