What can tumours in Tasmanian devils teach us about immunotherapy resistance?

A peculiar type of tumour, in an even more peculiar type of animal, could hold some clues to help scientists overcome immunotherapy resistance in humans.

Not many of us will have come across a Tasmanian devil in the wild – they’re only found on the island state of Tasmania. These creatures, similar in size to a small dog, are susceptible to a particular form of cancer, called devil facial tumour. And what’s unique about these tumours is that, unlike human cancers, they can be passed from devil to devil.

Tasmanian devils transmit the tumours by biting each other on the mouth, which they often do as part of a mating ritual. The cancer is almost always lethal, and with DFT now covering most of Tasmania, the future of devils in the wild is uncertain. Teams at the University of Tasmania Menzies Institute for Medical Research and School of Medicine are working to understand devil facial tumour in an attempt to conserve the population.

Serendipitously, this work could help cancer scientists understand why some people don’t respond to immunotherapy.

But first, we need to come back to the UK.

Cancer resistance and immunotherapy

In Cambridge, Dr Marian Burr and her colleagues were trying to understand why some immunotherapies were not getting the responses they were anticipating.

Immunotherapy treatments can work in lots of different ways, but they all aim to harness our immune system to fight cancer. Many target molecules on the surface of immune cells to help boost their ability to recognise and attack cancer cells.

But they’re not always as effective as expected.

“There are still a large number of patients who don’t respond to immunotherapy treatments and for the most part we still don’t understand the reasons for that,” says Burr.

To begin unpicking those reasons, the team homed in on a molecule that plays a vital role in our immune response, called MHC class I. This molecule helps immune cells identify and destroy potential threats, including cancer cells.

But some cancer cells find a way to evade detection, by removing MHC class I molecules from their surface. This could render them resistant to immunotherapy, by making them practically invisible to the immune system.

The big question the team wanted to answer was, how? Working with Professor Paul Lehner, they used gene editing tools to see what causes MHC class I to disappear from the surface of tumour cells.

“We were looking to see if there were any genes that we could take out that would put MHC class I back on the surface of the cancer cell,” says Burr. “And that was how we found the PRC2 complex.”

Publishing their work in Cancer Cell, a team led by Burr and Professor Mark Dawson at the Peter MacCallum Cancer Centre found that a group of proteins, called PRC2, could stop MHC class I appearing on the surface of some tumour cells in the lab.

The next step was to stop the PRC2 complex from doing this.

“In a range of cancers, particularly small cell lung cancer (SCLC), Merkel cell carcinoma and Neuroblastoma, we were able to show that by interrupting this group of proteins, MHC class I was put back on the surface of the tumour,” said Burr.

And blocking PRC2 activity in mice made immune cells more able to find and destroy tumour cells.

This isn’t the first time the PRC2 complex has been targeted. “Inhibitors are already in clinical trials in a range of different cancers,” says Burr. “And they have been fairly well tolerated.”

Burr thinks that the next step is to look at combining PRC2 inhibitors with different immunotherapies, to find the most effective treatment for cancers that have low levels of MHC class I.

Interestingly, other researchers in Cambridge had made the discovery that devil facial tumours had low levels of MHC class I too.

Which led the team to think – could the devil facial tumour also be using the PRC2 complex to avoid the immune system?

The devil in the detail

“As it is contagious, the devil facial tumour provides an extreme model of tumour immune evasion,” says Burr. To avoid being destroyed as they spread between devils, the tumour cells have evolved sophisticated ways to hide from the immune system.

And it turns out one of those ways involves our old friend, the PRC2 complex.

The team saw the same thing happening in Tasmanian devil tumours cells as in human cells and mice. MHC class I was being suppressed by the activity of PRC2.

The fact that PRC2 helps cancer cells evade the immune system in multiple species could be an indicator of how much cancer cells rely on this pathway to avoid the immune system. And resist the effects of immunotherapy.

“What we think is really important about this function of PRC2 is the fact that we see it in devils, we see it in mice and we see it in humans, which means it is highly conserved and is likely to be an important mechanism of resistance for the tumour cells.”

Ethan

Reference

Burr et al. (2019). An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer. Cancer Cell. DOI: 10.1016/j.ccell.2019.08.008