Regulation of T cells in tissues and tumours
Prof Adrian Hayday - King's College London, London, UK
We presented our work trying to understand the way that immune cells that sit within tissues respond to challenges to those tissues. The concept here is that the great burden of malignancy in human health is primarily the tumours, often called solid tumours, that grow within tissues – the skin, the gut, the lung, the liver. The immune system which is now acknowledged to have a significant inter-relationship with the development of tumours is not simply an immune system that comes from a centralised compartment, from the blood and from the lymph nodes, but the immune system actually already contains large numbers of cells within those tissues, even under normal circumstances. It seems rather essential to understand how those immune cells interact with these tissues under any form of circumstances if we’re then to understand how the immune system interacts with tumours that form in those tissues. So that was essentially the thesis of the presentation.
Do you know much about how they interact with tumours?
Yes, again, our whole approach has been to understand the normal biology of these cells and then to ask how the development of tumours in those tissues perturbs that normal biology. So interestingly enough, the existence of these cells and their special properties that relate to where they sit, for example T lymphocytes that sit within the skin are not the same as the T lymphocytes that sit within the gut and are not the same as the T lymphocytes that sit within the lung. This has been known for about a quarter of a century but the basis of this special intimate, as it were, inter-relationship between these T-cell compartments and their tissues was really not known and there were several groups that tried very hard to find ways to unpeel what were the key interactions that mediated that. Well, happily, by persisting with this question we began to get some clues about ten years ago, some genetic clues as to what might be the molecules that were regulating this.
Just this year we’ve completed the identification of molecules that mediate the interaction of specific tissues, for example mouse skin, mouse gut, human gut, with these very specific T-cell compartments. Now that we’ve identified those molecules we can now very specifically ask what happens in cancer and, of course, perhaps predictably, what we find in studies of colorectal cancer is that these molecules are seemingly very specifically reduced in their expression. That means that the T-cells that are sitting in the gut have reduced ability to monitor these cancers, at least that’s what we would predict. What’s good about that is it gives us a very, very clear and clean clinical target which is to try to re-establish that molecular access, as it were, in that targeted fashion. Now, it’s worth noting that the advantage, potentially, of this kind of approach over broad-based immunotherapies that are beginning to do so very, very well in many clinical scenarios, albeit with very, very significant burdens of adverse events, is that these molecular axes that we’re talking about here are extremely localised. So the idea would be that, for example if a lesion was in the gut, you could specifically manipulate immune regulation of that lesion in the tissue that was relevant, rather than blasting your systemic immune system and thereby unleashing potentially severe side effects, which is clearly the clinical experience to this point. So while things are going very, very well at the moment in the clinic, we hope that this more localised refined approach will prove to be the useful next step forward as we refine immunotherapeutic approaches.
What technology have you been using?
We use a lot of technologies. One of the reasons that I’m at the Francis Crick Institute is they have spectacularly powerful technologies at a molecular level and at a cellular level for looking in animal model systems where we can probe cause and effect in ways that you can’t do in humans. Conversely, one of the reasons I have a laboratory at Kings College London is the Guy’s, King’s and St Thomas’ Health Trust’s extraordinarily powerful and extremely knowledgeable centres for the provision of care. So we’re able to liaise with clinicians and very rapidly validate what we do in animal studies into human and back again into animal studies to do testing. So we’re very happy with that situation but it took a very long time to build that. It’s not typical to be in that position and that’s the sort of thing that actually needs a lot of attention. The other thing that we’ve benefitted from is the investment from the Department of Health in what’s known as biomedical research centres and that’s provided us with access to very high end flow cytometry, genomics and so on and so forth. So none of this would be possible without the capacity to harness state of the art approaches, both in model systems and with clinical samples.