Hannah Siddle, Cambridge University
Devil Facial Tumour Disease, the cancer spreading though Tasmanian Devil populations, is able to evade the immune system. New epigenetic studies show how...
Chris - What is special about this tumour tissue that when injected into a devil, by a devil (or perhaps even by a human if weíre to do that experiment) means that there isnít an immune attack against it because weíre out to take an organ out of me and put it into you? Is there really a high chance that there would be a very vigorous immune response?
Hannah - Yeah, that's exactly right, Chris. In humans, we know that we should, if we take a graft and we do a kidney transplant or something like that, we should get a very big and damaging immune response to that graft. But in the Tasmanian devil, we donít see a protective immune response to the tumour. In fact, we hardly see any immune response at all and I've been interested in why this is the case. And our most recent work, weíve actually shown that in the surface of the devil facial tumour disease (DFTD) cells...
Chris - Those are the tumour cells themselves.
Hannah - Yeah, the tumour cells themselves have actually changed some of the molecules that are on the surface of these cells and because they've changed these molecules, that means that they're invisible to the host devil immune system.
Chris - Alright, so are these the same molecules that in my cells, my immune system is looking at those molecules to see whether that cells, one of my cells, or if there's a virus in there, that kind of thing?
Hannah - Yes, that's exactly right. They're called MHC molecules or sometimes histocompatibility antigens and these molecules are found on the surface of nearly all cells, and they are the immune system signals. So, they send up flags to say that, ďNo, this cell is healthy. Donít attack this cell or to say this cells is infected by a virus or itís malignant, or itís foreign, itís non-self, attack it!Ē And actually gives an attack signal by the immune system. So, by downregulating these molecules by the DFTD, by the tumour cells, itís invisible to the immune system.
Chris - There are lots of viruses that use a similar sort of trick to buy themselves time so that the immune system doesnít realise there's a virus in this cell, but the immune system has kind of thought of that because it looks for cells that donít have these molecules and says, ďAha! They've been turned off, so there must be a virus in thereĒ so they attack it anyway. So, why doesnít the immune system then say, ďAha! Your tumour cells have got none of these moleculesĒ? They must have something wrong with them and wipe them out.
Hannah - Unfortunately, for DFTD and the immune response to DFTD, we donít understand fully that question yet. So, MHC molecules interact with one part of the immune system called T-cells and they signal to T-cells that either a cell is unhealthy or healthy. What you're talking about is done where there's a downregulation of these MHC molecules either by a tumour cell or by virally infected cell. That sends a trigger to what we call NK cells to attack the tumour cell. And we donít actually understand yet, why NK cells donít attack the DFTD cells, but that is something that we are working on.
Chris - But one thing that you presumably have got to the bottom of, if you now know these molecules arenít there is, why they're not there. So, what's responsible for causing them to disappear from the cell surface?
Hannah - Yeah, that's right. So, in cancers, we often have what we call hard mutations in cancer genomes or soft mutations. Hard mutations occur in the gene and they're actually, usually, like a deletion in the gene or some sort of change in the gene that means that that particular gene itís not expressed. Now, when we went and looked at the genes that encode NHC molecules in the DFTD cells, we found that we couldnít actually find any hard mutations. So, we couldnít find any structural changes in these genes that would explain why they're not expressed in the DFTD cells. So, this was a bit of a mystery, but what we found is that it seems as if these are what we call soft mutations or epigenetic changes on the genome that's allowing the downregulation of these genes by the DFTD cells.
Chris - This is where you add chemicals or remove chemicals from the proteins that the DNAs wound around or sometimes the DNA itself to affect whether or not genes get turned on or off. But you can look for those, can't you? So, if you go hunting and look at the genes that encode these immune molecules, are they epigenetically different to a normal cell?
Hannah - That's what weíre looking at at the moment and it does seem as if they do have some epigenetic changes in these genes that's actually silencing the genes, causing them to be turned off. And if we treat the DFTD cells with epigenetic modifiers, we can actually increase the expression of these genes again. Actually, that's probably one of the most exciting things about this finding, is that because these changes are what we call soft changes or they're reversible, we can actually in the lab, restore the expression of these MHC molecules to the DFTD cells. We think that that could have really important consequences for developing a vaccine to the disease.
Chris - Because you'd give them a drug that turns these molecules back on, enabling the immune system to see the cancer which was previously cloaked in this sort of invisibility shield. It would come back to the attention of the immune system which will then presumably deal with it?
Hannah - Exactly and an alternative is that we can, by treating these DFTD cells in the lab, we can engineer them to express MHC molecules on their cell surface, and then we can put them back into the devils. So, weíre putting back in DFTD cells that have a signal to the immune system of, ďWeíre unhealthy. Weíre foreign. You need to attack us.Ē
Chris - This must be music to your ears, Elizabeth?
Elizabeth - Yeah, very, very exciting work.
Chris - How do you see this being applied?
Elizabeth - Well, weíre all hoping that perhaps this will lead to a vaccine that can be delivered in the wild to protect devils from succumbing to this disease.
Chris - Do you think itís realistic?
Elizabeth - I think so. I think there's still quite a lot of research still to be done, particularly on why it is that the tumour can get established in a devil that's got a healthy immune system. And I think that understanding in more detail how the immune system is not able to attack it will be very important before we can develop a vaccine.
Chris - And Hannah, what can we learn about ourselves and possibly doing better organ transplants from studying what is going on in these devils because they're effectively doing an organ transplant that is not being rejected, arenít they?
Hannah - Yeah, that's right and there's that aspect of it and there's also the fact that this is a cancer that is a master at invisibility. And so, not only is invisible in a single animal, but itís invisible each time itís being passed through into a different individual. And so, the mechanisms that itís evolved in order to escape the immune system are very, very sophisticated. And so, I think we can learn a lot about how a cell is immune privileged and how it can disguise itself from the immune system.
Hannah Siddle and Elizabeth Murchison, both from Cambridge. Thank you very much.