About the guest: Caetano Reis e Sousa, DPhil is an immunologist and Principal Group Leader at the Francis Crick Institute in London. His lab studies immune system function, including its ability to fight infection and cancer.
Episode summary: Nick and Dr. Reis e Sousa discuss: dendritic cells & innate immunity; how the immune system recognizes pathogens, damaged cells, and cancer cells; gut microbiome & non-pathogenic bacteria; inflammation; vitamin D & gut-immune interactions; cancer; and more.
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Episode transcript below.
Full AI-generated transcript below. Beware of typos & mistranslations!
Caetano Reis e Sousa 3:32
Yeah, sure. So my name is Caetano Reis e Sousa. I am a principal group leader and an assistant research director at the Francis Crick Institute, which is a large multi disciplinary Institute in London. I also have visiting more honorary professorships at the Imperial College, King's College and University College, which are three large universities, again based in London, and my lab is called the immunobiology laboratory, largely because we didn't want to pin ourselves down too much, and that gave us the sort of latitude to study various aspects of the immune system. But if I had to summarize it, I guess the key issue that interests us is how the immune system detects the presence of potential pathogens, of cancer cells, or even just changes in tissue homeostasis, for example, injury, And how, in response to that detection, it puts in place appropriate mechanisms to restore homeostasis. And so we think of sensing at two levels. We think about what are the cells of the immune system, and not only of the immune system that might be involved in. Sensing. And then we think of sensing at the level of molecules. So what are the molecular pathways, receptors and otherwise, in those cells that operate to detect those changes in homeostasis brought about by infection, cancer or tissue damage?
Nick Jikomes 5:21
And so it sounds like you're studying the innate immune system, so the portion of the immune system that is sort of the first line of defense that responds automatically and doesn't necessarily need to learn or adapt to a pathogen or something like that.
Caetano Reis e Sousa 5:36
That's correct. So it's very much centered on innate immunity. But actually, what we are mostly working on is that a bridge between the innate immune system and the adaptive immune system, namely, when that immediate early response is no longer sufficient to contain the infection or the tumor, and you need to call in T cells and B cells. And so these are innate immune mechanisms that are shared by a large number of cells, but that is one cell type, one innate immune cell type, white blood cell called a dendritic cell that has this specialized function of translating that innate information into an adaptive response. And the reason we we focus much of our attention on those cells is precisely because we think there is some decision making there that will probably probably be quite informative in terms of telling us how the immune system works and how we can co opt those workings for therapeutic benefit. And
Nick Jikomes 6:53
my understanding is, you know, we're probably, there's probably bacteria and pathogens getting into our body all the time, they're just often not at a level where you require a full blown adaptive immune response. So I would imagine things like dendritic cells, if they're if they're just running into one or two bacteria cells, they can sort of handle them on their own, and they don't need to call in for reinforcements, so to speak. Is that is that part of the equation here? Can the innate immune system sort of handle low level infections before they get too big, and it's only after they get overwhelmed that that decision to call in reinforcements needs to happen.
Caetano Reis e Sousa 7:31
Well, I mean, that is one possibility, but the the the real answer to your question is that we don't quite know what are the parameters that dendritic cells effectively integrate to decide whether to call in the sort of T cell and B cell arm of the response or not. Abundance of the bacteria may not be the only factor. I mean, we talk about pathogens, but the reality is that we are in inhabited by very large numbers of commensal bacteria. And in fact, there can be a very large burden of bacteria in parts of the body where there are dendritic cells. And yet the this does not necessarily result in a T cell response, or at least a canonical T and B cell response, such as the ones that we associate with protection from infection. So I think the rules of engagement are still not fully understood. And there is this idea, perhaps, that it is not just about detecting the presence of the bug, but it is about detecting something that the bug might be doing, and that will be the difference between a commensal and a pathogen. And actually, a commensal can become a pathogen if it invades and does not respect boundaries and does starts to cause damage, and perhaps dendritic cells and perhaps other cells can detect some of those hallmarks of pathogenicity, and that goes into their decision making process.
Nick Jikomes 9:14
And so can you give us an idea for what we know about how dendritic cells actually recognize things like pathogenic bacteria. There must be some kind of molecular recognition system that allows it to distinguish between our cells and and and pathogens. And, you know, actually, just thinking about it right now, like when I think about the molecular diversity of all of our own cells, you know, skin cells, nerve cells, stomach cells, and so forth. And then on top of that, all of the molecular diversity of other cells, like all of the different bacteria out there. It's sort of astonishing that they could even start to make those discriminations. And I wonder how they do that.
Caetano Reis e Sousa 9:52
Yeah, so, so one thing is, how do they discriminate between, say, a bacterium or a fungus in our own cells that will not you? Necessarily tell the dendritic cell that it is a pathogenic bacteria, more a pathogenic fungus, but just that is something there that is not your own cell, and that is relatively easy, and that is this concept of pattern recognition and the pattern recognition receptors. So these are receptors that dendritic cells and other cells possess, and they detect signatures of microbial metabolism that are not made by our own cells. So for example, bacteria will have capsules with capsular polysaccharides that are only made as a result of bacterial metabolism. So if a if you have a receptor that detects those structures, or, for example, a fungal beta glucan, then you know that it's got to be a bug that's present, because we don't make beta glucans or those polysaccharides. So that's a fairly straightforward way of knowing that something is of non human origin, if you will. That doesn't necessarily then tell us whether it's going to be pathogenic or not. And that goes back to this more complicated question of whether these dendritic cells might be integrating other signals. So you could, for example, envisage, and this is an idea, as opposed to formally proven, that the dendritic cell could detect that that bacterium is growing and is also causing death of tissue cells, and so the dendritic cell could detect the coincidence between the presence of the bacterium and the presence of dead cells, and that would indicate that something atypical is going on. Or in some particular cases, there are pathogenic bacteria that do have some determinants of pathogenicity. So for example, some bacteria have these needle like structures that can actually inject bacterial substances into host cells for to allow the bacteria to take hold and propagate. And those will be features of pathogenic bacteria that would not be present on commensal bacteria. And so you could also detect the presence of such structures. And so that's probably a very large combination of features that are being detected, including integration of signals from other cells. So the dendritic cells are not just necessarily detecting the microbes themselves or the viruses, but also responding to signals from cells that have encountered those bacteria or viruses. So
Nick Jikomes 13:02
it sounds like there's there's some easy ways to detect when something other than a human cell has gotten into the body. There are certain molecules that are only going to be present on bacteria and other types of creatures, and those are easy to detect. But knowing that alone is often not enough, because you don't know if it's going to be a pathogenic bacteria or a commensal bacteria, as you mentioned. But there are other signals on some pathogenic bacteria that do clearly identify them as pathogens, literally, these needle like structures that can poke into cells. So there's there's a mix of signals. Some of them might just tele dendritic cell, okay, something's in here, may or may not be bad. There's other signals that say, Okay, this, this is definitely a bad guy, and so forth.
Caetano Reis e Sousa 13:49
That is absolutely correct. And the other thing to remember is that ultimately, the arbiter of the response is going to be the T cell or the B cell. In other words, the dendritic cell is a sort of clever Sentinel, but in a way, it's a little bit of a blind Sentinel. It will present various things, and the fact that it presents these things to T cells, then, doesn't necessarily mean that those T cells will now respond, so those T cells themselves will now be integrating additional signals. So for example, there are T cells called regulatory T cells, which could come into contact with the dendritic cell and say, Yeah, I mean, I know that this is a commensal bacterium. I've seen this before, and that's why I've become a regulatory T cell, because I don't want our body to be. Responding to these commensal bacteria, and that could then, if you will, suppress the response of any other T cells that might want to join the party and do and create a full blown response. So it's not only about that dendritic cell, but a whole constellation of signals that then, then integrated where T cells and dendritic cells congregate, which is in lymphoid tissues, like lymph nodes
Nick Jikomes 15:30
I see, I see, so there's multiple layers of checkpoints that determine what the immune response will end up being, assuming things are all working properly. And you said that the dendritic cell shows the T cells stuff that it's finding out in the peripheral parts of the body. How does that happen is, is the dendritic cell literally like engulfing a potential pathogen and then digesting it and presenting components to the T cells?
Caetano Reis e Sousa 15:58
That's precisely the case indeed. In fact, I mean, what the dendritic cell does is it solves a huge topological problem you have in your T cell repertoire, you will have many, many T cells, each one with a slightly different fine specificity. So amongst your T cells, there may be just maybe 10 or so T cells against the new bacterium that you have encountered. Now, those T cells are traveling around the body, and that bacterium could be anywhere. And so what you need to do is solve this spatial problem of, how do you ensure that the two come together, the one that the T cell that's got specificity and the bacterial bits that they can see? And so the idea is, basically they have relay stations so you circumscribe all your T cells to continuously recirculating amongst your lymphoid tissues, for example, your lymph nodes. So these are like so rest stations, and they constantly go from one to another. And so in 24 hours or so, they might cover all of these lymph nodes which are strategically positioned around the body as receiving platforms into which dendritic cells, which are positioned everywhere in the body, can then migrate, bringing in bits of the things that they've encountered. And so if your bacterium actually came into contact with the dendritic cell in the skin, the then T cell doesn't need to be in the skin to see it. The T cell ends up in a skin draining lymph node, and the dendritic cell travels to that lymph node, and that's where they will encounter, and you're completely right. What they really encounter encountering is a small fragment of that bacterium or that fungus or that virus that the dendritic cell is presenting to that T cell.
Nick Jikomes 18:10
And so, you know, you mentioned that you know for dendritic cell to detect, say, a bacteria, that's a relatively easy problem. Bacteria cells are very different from human cells, so they have these fairly clear molecular signatures that the dendritic cells can readily detect. Something that's a little bit harder for me to think about, at least, is, how does the immune system, how does something like a dendritic cell identify, say, a damaged tissue, a damaged cell that's of our own body, or, say, a cancer cell, or something like that.
Caetano Reis e Sousa 18:42
Yeah. So let's start with a damaged cell. I mean, you're right, a damaged cell will be identical in composition to a normal cell, but what we will have that will be different is that it will be exposing its innards, because, by definition, a damaged cell is a cell that has lost its integrity, and so this fine membrane, called the plasma membrane, that separates the cell from the extracellular milieu, has somehow been damaged and that allows the contents of the cell to be displayed. And so a very simple strategy, which is one that we have worked on for many years, is for dendritic cells to possess receptors that specifically bind to the innards of cells. Now technically, those innards are also in the dendritic cell itself, but if the receptor faces the outside, which it does in the case of the dendritic cell, you have a receptor that faces the outside if it comes across some of these innards, and in particular one that we have focused a lot of attention on. Is the actin cytoskeleton, which is part of the sort of framework of a cell that gives it rigidity and allows it to to undergo motility in various cell processes, all cells have an actin cytoskeleton, and that actin cytoskeleton is never exposed to the extracellular milieu. Dendritic cell, possessing a receptor that recognizes the actin cytoskeleton, will only see that receptor engaged if it comes into contact with a damaged cell or a cell debris, and that is a universal sign, because this actin cytoskeleton is present in all cells. Any cell that's damaged, irrespective of whether it's a liver cell or a skin cell or even a red blood cell, any exposure will any damage will result in exposure, and that will be a universal sign of cell death or damage. So that is one of the ways in which this can be recognized. Now, cancer cells, however, we believe, are partly recognized in this way. We believe that as cancers grow, there is often a lot of cell death. Cancers, as they quickly grow, they can outgrow their blood and oxygen supply and nutrient supply, so they can effectively, often display signs of death. And so this is one of the ways in which they could be recognized, and we think that it is one of the ways in which anti cancer responses can be elicited immune responses. But there are probably a number of other mechanisms in the process of conversion to a cancer cell from a normal cell, what cancer biologists call transformation. There are quite a number of changes that go on in the cancer cell, and they can result in display of molecules that are not displayed in normal cells. And those can be actually signs of cellular stress, and they may not even have evolved to denote the presence of a cancer cell. They may, in some cases, they appear to have to overlap with signals that cells put up when they are infected with viruses. So we've been discussing a lot about bacteria and fungi and how easy it is for the dendritic cell to recognize those molecular signatures of those microbes. For viruses, it's a different ball game, because they effectively replicate in the host cell. And so a cell infected with a virus is not going to be all that different necessarily, from a cell that is not infected, but the evolution appears to have created a system whereby an infected cell knows it's infected and can put up Some signs of infection. It can also secrete some molecules that activate cells of the immune system, including dendritic cells. And it is a lot of that may overlap with signals that are put up when cells become transformed and become cancer cells. So there can be sort of mechanisms for detection of virally infected cells, as well as cancer cells that are used by the immune system to generate immune responses.
Nick Jikomes 23:53
So in the case of damaged tissue, if a cell is damaged, its membrane will be disrupted in some way, say, and stuff that's normally trapped on the inside of the cell can become exposed and and a dendritic cell can detect that the external environment. I guess it might be akin to like, you know, if I break, if I break, my arm and my bone is sticking out through my skin, someone can see that. They can feel it. They can detect it with their senses. Something that's normally on the inside of my body is now outside, and for a damaged tissue, something like that is happening at the molecular level, where the cytoskeleton, the molecular skeleton of a cell, becomes exposed. And that's actually what the dendritic cell is sensing. That's
Caetano Reis e Sousa 24:31
absolutely right. And the analogy goes further, which is that you it's important to have things that don't just very quickly diffuse away, then remain associated with that corpse or those debris, because then the dendritic cell needs to identify where that damage actually is. So if it was something that just leeches out of the cell very quickly, it can serve as. An alert signal that something is going on. And in fact, those molecules do exist. They are part of the system that that is detected, or part of the signals that are detected by our innate immune system to indicate that something is not quite right, but the ability of the skeleton of the cell to remain associated with the debris gives an indication of where the action needs to be focused on. And
Nick Jikomes 25:33
then, in the case of cancer cells, even though they are our own cells, they have been transformed in some way. They're now different, and part of that involves developing molecular signatures that can be recognized, I would imagine, probably not unlike the way that the dendritic cells recognize bacterial cells, there's some molecular marker on the outside that can be recognized that is abnormal.
Caetano Reis e Sousa 25:58
Yes, the perhaps the slight nuance there is that often, when we're talking about those sorts of things, it is not quite as qualitative as in the case of bacteria, in the case of bacteria and fungi, it really is a qualitative difference, because those molecules are never made by our own cells. In the case of cancer, is often a quantitative phenomenon, which is that maybe putting up more or less of certain molecules, and that's a subtle difference from a normal cell, and so the immune system can recognize it, but is perhaps a little bit trickier. And
Nick Jikomes 26:40
you know, one of the things I'm very interested in that I know that you've studied in different ways, is the relationship between metabolism and nutrition and immune function at a very high level. I'm wondering if you could paint a picture for us here. So I would imagine that, say, in an active infection, a lot of resources have to be deployed to combat the infection. I would presume that this whole calling in the army, so to speak, is going to be very resource intensive, and there's going to be a lot of metabolic need to operate the immune system and get it to where it needs to be. There's probably going to be a lot of nutrient turnover and nutrient need to power that whole process. Can you give us just a bird's eye view of how metabolically intensive an immune reaction is.
Caetano Reis e Sousa 27:24
Yes, I mean, in fact, we can use PET scans, for example, to detect sites of glucose consumption, and the brain always lights up in a normal individual, because that's a site of high glucose consumption. The other place that also often lights up is areas of inflammation, in addition to also tumors, but areas of inflammation where you've got lots of immune cells fighting infection, or, for example, in autoimmune disease, can also light up so there are high metabolic needs, and the cells of the immune system can often switch them metabolism. They are reasonably flexible, and in fact, some of these signals from these pattern recognition receptors that we were discussing earlier can actually tell the cells to switch their metabolism, so for example, to become to instruct dendritic cells and cousins of dendritic cells called macrophages, to preferentially use glycolysis, because that is a way of very rapidly generating energy, even if you don't extract quite as much ATP per molecule of glucose as you do with other processes. So there is, and then we also learning that a lot of these metabolic pathways in these cells are themselves producing signals that come out of metabolism and that act as signals for the that can modulate the immune response and modulate this process of inflammation
Nick Jikomes 29:26
I see. So there's a lot of metabolic flexibility baked into some of these cells, and that makes intuitive sense to me, because you know, if, say, a pathogenic bacterial infection is breaking out, you have to detect that infection, and then you have to quickly, as quickly as possible mobilize cells to come respond to it. So it would make sense to me that a cell might want to switch its metabolism to quickly utilize energy as fast as possible and start doing different behaviors than it was doing previously.
Caetano Reis e Sousa 29:53
Now, correct and also when we then come onto the sort of T cell and B cell side. The things, these very rare T and B cells that are able to recognize that particular bacterium that the dendritic cell is presenting to them, they now have to multiply very rapidly and create a whole army of clones that can then effectively efficiently help eliminate the pathogen, and that itself also has very large metabolic requirements, and not just in terms of energy, but obviously in terms of generating all of the building blocks to make lots of daughter cells very, very rapidly. So you need to generate all the protein material and lipid material and what have you so that you can actually go through the cell cycle, through cell division very, very rapidly. And in fact, you know, in a period of, you know, eight hours T cells can divide, which is a phenomenally high rate of cell division compared to some other cells. And that is really something that happens on demand when an immune response is evoked. And
Nick Jikomes 31:20
the fact that you can get that much proliferation, that much change, that quickly, it's a very demanding process. Obviously. Are there any specific nutrients, or classes of Mac macro nutrients that are sort of rate limiting for this whole process? So for example, are, I don't know, our essential amino acids, one of like the rate limiting things, because you really need them to build up this army of new cells. Or is, does it even make sense to talk about individual nutrients that might be rate limiting? Here is the whole process just so intensive that you sort of you need some of everything.
Caetano Reis e Sousa 31:58
I again, without being a great expert in the field of metabolism and immunity, my understanding is that you need a lot of everything, and some things may be more rate limiting than others, but you know, by and large, you can, I mean the reality is that we know we can evoke those responses very rapidly, very efficient in people, and in fact, acutely in response to vaccination, we see that the great majority of individuals response, and I do not know of any information that may just reflect my ignorance, saying that there's a particular nutrient that could be limiting, say in vaccinees, in terms of the response they will elicit. So
Nick Jikomes 32:56
this whole process is very demanding, metabolically. A lot of things happen astonishingly quickly. The fact that we can get so much cell division and so much changes is remarkable. And you know, in terms of the innate immune response and the dendritic cells detecting cells and and presenting them for for interrogation to the T cells, I'm curious. Like to go back to this idea that, okay, there are pathogenic bacteria that we want to get rid of as soon as we can, when they enter our body. But as you mentioned, there's many, many species of bacteria that are helping us, that are or that are neutral, um, they're very abundant. They're constantly there. They're constantly, presumably, bumping into dendritic cells, and yet they don't elicit an immune response. What can you say about that things like the gut microbiome? How is it that that we have this whole sort of ecosystem of bacteria in our bodies that are sort of supposed to be there, in some sense, and yet they're not triggering an immune response?
Caetano Reis e Sousa 33:56
Yeah. So one of the things that was sort of glossed over is that we talk about eliciting an immune response or not eliciting an immune response. In fact, that's not really the decision that's made in the great majority of cases. There's a huge element that has to do with the quality of the immune response. So immune responses come in multiple flavors, and the commensal bacteria, for a long time, were thought to just be ignored. You know, they're not really doing any damage. Dendritic cells are aware, perhaps, of their presence, but they're not really, you know, they're peacefully coexisting, and we have this sort of immune ignorance of this large burden of bacteria that turns out not to be quite correct. And in fact, it is apparent that dendritic cells are constantly sampling those commensal bacteria and actually showing them to T cells and B cells in eliciting a response. It's just not a.
Nick Jikomes 40:00
Integrity of the physical mucosal barriers that separate or demarcate the boundary between the lumen of the gut where the commensals are supposed to be, and then the interior of our bodies, where they're not supposed to get into. If that starts to break down, they're going to invade into the body more often, and then this would naturally just trigger a larger and or more chronic immune reaction,
Caetano Reis e Sousa 40:22
and you're quite correct, because there are instances of inflammatory bowel diseases which can be mapped back to defects in the adhesion molecules that keep those epithelial cells tightly together. So that is certainly one of the problems that you can have weakening of the barrier. Or, you know, chronic weakening of the barrier can permit this translocation of bacteria, and that creates, then a much more robust response, which then creates a lot more collateral damage. So we're going back to this issue that you're tuning the quality of the response and the quantity of the response to effectively try and achieve your aim, be it to keep the commensal contained or to eliminate, but at all times trying to minimize collateral damage. And when these mechanisms start to fail, that collateral damage can then manifest itself as chronic inflammation or even autoimmune disease.
Nick Jikomes 41:36
And you know, one thing that's occurring to me here is that when we when we have inflammation in our everyday lives, whatever it may be, whatever its origins may be, when we experience it as people, and we experience the discomfort and the pain and so forth, we often naturally and reflexively go for an anti inflammatory solution, whether that's taking medication or putting ice on something, or what have you. But it occurs to me too, based on what you just said, that you know, just to take, let's just keep with the same example we were talking about. Let's say you have a breakdown in the mucosal barrier in the gut lumen, and so now you get commensal bacteria coming into the body that are not supposed to be going into the body, that are supposed to be contained in the lumen. If you have an inflammatory response to that, say a chronic inflammatory response, because it keeps happening recurrently, the problem there isn't the inflammation per se. The inflammatory response is, you know, supposed to be happening, and the problem is that you have a mucus barrier issue that's enabling bacteria to get in to trigger an immune response. And I wonder if there are conditions like that that are inflammatory, where actually taking anti inflammatory medications or something might not be a good idea, might actually be a bad idea. Does that make sense?
Caetano Reis e Sousa 42:52
Well, it does make sense. But the reality is that in some cases, the the reason why that barrier may be weakened is because you of a genetic predisposition. I mean, let's just go back to the example where perhaps the adhesion molecules between your epithelial cells in the gut are a little bit weakened because the genes that you have that encode those encode variants that are perhaps not as strong as others. There's not much that you're going to be able to do about those genetics. That's always going to give you a weakened barrier, and that's always going to give you a little bit more microbial translocation. And it's clear that the immune system is not able to completely eliminate that because it's chronic. Now, I think in those conditions, you could say, well, what's worse? To have a little bit of translocation or to have the cholesterol damage of that continuous immune response, and this is where the anti inflammatories then become key, because you're basically just saying, Well, what I can't really live with is the collateral damage that's causing me, the disease and the discomfort.
Nick Jikomes 44:10
What about, before we get into some some other topics, I want to talk to you about. What about so, so, just something very basic that we've probably all experienced, you know, when I was when I was when I was a boy, all throughout my life, if I bump my knee or I get a bruise or something, or there's some swelling from an injury, when I'm playing sports, say, or playing outside, the immediate response was typically to put ice on it to contain the inflammation. But if the inflammation is sort of supposed to happen, to clear out the debris and stuff, how do you think about that? As an immunologist. If, I don't know if you have children, but if your child bumps their head or their knee and they have an inflamed portion of their body, what? What tells you whether or not to put ice on it or to sort of let it be inflamed for a while?
Caetano Reis e Sousa 44:53
Yes. I mean, that's a good question, because, as you point out, inflammation is a. A key part of the reparative process that is immediately put in place in response to injury. And so when we put eyes, or we take some of these anti inflammatories, for example, to decrease production of prostaglandin e2 then very often we alleviate those symptoms. But does that actually somehow delay the reparative process or impair it? I don't actually know the full answer to that. However, the experience that we all have is that it gives us, you know, a better quality of life. And so even in those acute cases where perhaps it wouldn't be absolutely essential, the that doesn't seem to be a profound disadvantage to having it. And maybe you could argue that if you hadn't taken it, it would have resolved a little bit quicker, but then you would have had your kids screaming for 24 hours. Though you've got to take balance all of these things in making that decision,
Nick Jikomes 46:22
I see, I want to get to some of the recent research you've done, and some of the background here that I think is relevant is we've talked about the microbiome already. I've done a number of episodes about the gut microbiome, so I'm not sure how much background we need to do there. But obviously we have a gut microbiome. It's very important to different ways. And the immune system ties into this for for the reasons we discussed, the immune system is there to sort of monitor and keep the gut microbes where they're supposed to be, and to determine how some of that happens. One of the nutrients that I know, that you've looked at that's going to be relevant here is vitamin D. And I want to have a fairly general discussion before we get into the findings. Vitamin D is quite a famous nutrient. Everyone's familiar with it to some extent, most of us, my understanding is most of us, are apparently vitamin D deficient most of the time these days, for reasons that aren't entirely clear to me. And vitamin D is very important for a number of processes in the body, and I believe it's important for immune system function generally, although I don't really know much about that. So what is vitamin D doing that's relevant to the immune system?
Caetano Reis e Sousa 47:25
So I should say that our recent work that has led us to vitamin D was one of those serendipitous discoveries in science. We were not interested in vitamin D whatsoever, and we had never really worked on vitamins or nutrients or even the microbiome, and for various reasons which actually have to do with the ACT inside the skeleton, which we were studying, these sort of signals of cell death recognized by the dendritic cells, which we discussed earlier for we were looking for mechanisms by which the immune system might modulate its response to this, This actin skeleton of cells, and we stumbled upon a protein that was modulating vitamin D availability. So there is a very, very long history of vitamin D and everything, vitamin D immune system, vitamin D in cancer and vitamin D in health in general, and I don't really want to get into because, you know, a lot of those studies are quite controversial, and some you will find evidence for all sorts of different ideas. The only thing that I can say with respect to vitamin D is our own work, where we serendipitously found that vitamin D was increasing the resistance of experimental mice to challenge with cancer, And we thought that this was something rather odd. We, you know, we that's not what we were studying. But once we found it, we decided to get to the bottom of it. And basically, what we ended up finding is that a very convoluted, if you will, mechanism by which what vitamin D is doing is modulating the microbiome, the composition of the microbiome, we think, allowing for some bacterial species to thrive or do. A little bit better than others, and in turn, those bacteria were instructing our immune system to be more responsive to the presence of cancer. Now that raises a lot of interesting questions, some of which relate to what we were already talking about. Now we said that the immune system does not ignore these commensals, and, in fact, actively keeps them at bay, albeit with a atypical response that does not cause elimination. But it turns out that our immune system is also being conditioned by those bugs. So there is a sort of dialog going on where things that made by those commensal bacteria in our guts, and perhaps commensal fungi or even commensal viruses, are putting our immune system on different states of alert, and that can have an impact on immune responses elsewhere, in this particular case, in immune responses to cancers that are nowhere near the gut. And what vitamin D is doing is impacting this dialog indirectly by effectively allowing some bacteria to thrive that make some more of, perhaps of the compounds that put the system on a cancer alert state. And the way that vitamin D is doing that is actually by acting on these epithelial cells of the gut that we were talking about, the ones that form the barrier. And those epithelial cells of the gut are not just passive components of the dialog between the commensal bacteria and the host. They are active participants because they can make little molecules that get incorporated into that mucus and that help keep the bacteria at bay, and that may favor some bacteria versus others. So in a nutshell, the complex, what seems to be happening is vitamin D acts on epithelial cells. Epithelial cells make something or or stop making something. We don't quite know that changes, helps change the composition of the gut bacteria. This is all in mice. I should say that altered composition now changes the dialog with the immune system. The immune system in response to whatever signals are made by whichever bacteria thrive when Vitamin D has acted on the epithelial cells that immune system is now more responsive when we challenge mice with a cancer. So just to be clear, this has all been done in mice, and to what extent this is all applicable to humans, we don't know, but it did lead us to sort of ask a little bit about vitamin D and human cancer, and we were lucky to actually be able to collaborate with some colleagues in Denmark who had access to a very, very large database of health records of the Danish population. You alluded to the fact that vitamin D can be limiting for many people, and because it can be made by sun exposure, populations that live at more northern latitudes, like Denmark, tend to experience more of a vitamin D winter. So vitamin D may be more limiting for those populations, and what we were able to do is stratify people from the Danish population into those that had high, low or deficient vitamin D based on a single blood test. So there's caveats to this, because we don't know what they did after that blood test, they could have taken supplements to correct any deficiency that could have been detected. But nevertheless, we had one and a half million people. We could divide them into these three categories, and what we found is looking at their health records, is that those that had once been diagnosed as vitamin D deficient over the following decade, had a higher risk of developing a number of cancers compared to those that were not vitamin D deficient. Now that's the extent really of our human correlate. It's just a correlation in humans. In mice, we can prove all of these connections that I've just told you about in humans, we can only observe and correlate, so we do not know to what extent we're dealing with the same issue of somehow the vitamin D affecting the microbiome also in humans.
Nick Jikomes 55:19
So on the basic biology side, the stuff that you did in mice, so it sounds like maybe a way to think about this is the immune system is constantly monitoring the gut it's constantly in dialog with all of the bacteria in the gut microbiome, and the specific composition of bacteria in the gut microbiome. How many are there, which species are the most prevalent? This is going to affect the general behavior of cells in the immune system. So by analogy, I might imagine, like in my own life, I might have a conversation with someone, and this has a calming effect on me. I might talk to somebody else, and they provoke anxiety. And you know, the state they put me in through my dialog with them, is going to affect other aspects of my life. I might be, I might be more likely to, you know, trip, trip and fall, or be a little bit more cautious, depending on who I was just speaking to. And so the composition of the gut microbiome is going to sort of determine the readiness, or the propensity of the immune system to be on high alert or lower alert for cancer cells, and so by modulating the composition of the microbiome, the vitamin D status of mice, at least indirectly, influences how readily the immune system is prepared to detect cancer. Basically,
Caetano Reis e Sousa 56:33
that's a very good analogy, and I think it's a pretty apt analogy. The only thing I would add to it is that we don't even know if it's merely the composition, ie the people that you encounter, or maybe the clothes that they are wearing. So maybe the same person wearing a red shirt will give you more anxiety than that person wearing a blue shirt. And so it could be as subtle as that, not just the people who are there, but what they are wearing, or some other aspect of their appearance,
Nick Jikomes 57:04
interesting. And then, you know, we suspect this could be at work in humans, but hasn't been proven yet, but you've at least shown that there is a correlation between the vitamin D status of certain people in certain parts of the world and cancer rates.
Caetano Reis e Sousa 57:19
Yes, and the only other piece of human data that we were able to get at is to sort of indirectly measure the genes that are induced by vitamin D in their cancers, where they have had the cancer biopsy, and try and correlate that with outcome and responses to immunotherapies. And again, the you know, by that sort of somewhat indirect measurement of their vitamin D status. Again, we came to the conclusion that it was having a higher vitamin D status led to better outcomes.
Nick Jikomes 57:58
And are these for all of this stuff, are there specific forms of cancer that you guys were looking at, or is it a general phenomenon?
Caetano Reis e Sousa 58:08
It was actually quite general. Looking at these human populations, there were a number of cancers for which we didn't see any correlation one way or another, where we did see a correlation across a number of different cancers, it was always that vitamin D insufficiency correlated with worse outcomes, ie, increased incidence of cancer. The only cancer for which we saw the inverse was skin cancer. But skin cancer is a confounder, of course, because skin since exposure the light gives you vitamin D, but it also is a risk factor for cancer, we suspect that that could explain why we saw an inverse correlation there, and in that case, the vitamin D might be have been a indication or a marker of sun exposure more than anything else. So we actually excluded those data from this type of analysis.
Nick Jikomes 59:13
And do we know much about what exactly vitamin D is doing within cells mechanistically to elicit this whole pattern?
Caetano Reis e Sousa 59:23
No, we don't. I mean, using mouse genetics, we found that it was acting on gut epithelial cell. Came as a little bit of a surprise, and so vitamin D acts on a receptor called vitamin D receptor, not surprisingly, and what we basically found using mouse genetics is that if we took vitamin D receptor away from epithelial cells, then the whole benefit of vitamin D went away. So what. Exactly it does there we don't know, and how exactly whatever it does then modulates this composition of the microbiota that we don't know. These are all areas that we are sort of exploring at the moment.
Nick Jikomes 1:00:15
So vitamin D is, is itself a signaling molecule and its receptor? Is it an extracellular receptor that's that's in the cell membrane?
Caetano Reis e Sousa 1:00:25
No, it's not. So vitamin D receptor is part of this somewhat small family of receptors that lives inside the cell, the nuclear receptors, so they the vitamin D actually diffuses into the cell and binds to the receptor in the cell
Nick Jikomes 1:00:43
I see. So that actually makes sense. Vitamin D is fat soluble, so can actually get into the cell Exactly.
Caetano Reis e Sousa 1:00:50
Yeah, interesting. I mean, the other parameter that we've sort of identified here is that, because vitamin D is fat soluble, it is a carrier protein in the blood. That protein is called GC globulin, and it was actually when we looked at mice deficient in GC globulin that we found this whole phenomenon, which was rather unusual and but it is interesting, because it turns out that the GC protein, or the gene that encodes the GC protein, is very variable amongst us Humans, so it has lots of different variants, and there are studies that associate certain variants with vitamin D deficiency. So actually, it turns out that it's not only about exposure to light which can allow our skin to make vitamin D or active vitamin D is not just about diet, which is another source of vitamin D, but then your own ability to transport vitamin D and the genetics that you have in terms of the vitamin D carrier might all come into Play. So if we're then thinking about human disease or human health. I think it's going to be a very complicated thing to dissect, because you have to take all these different factors into account. Wow,
Nick Jikomes 1:02:30
yeah. So it's not just about vitamin D synthesis or vitamin D supplementation. Your body's ability to actually transport the vitamin D through the blood to where it needs to go is going to be a major player here, and there's a lot of genetic variability in how effectively our bodies do that
Caetano Reis e Sousa 1:02:47
correct what?
Nick Jikomes 1:02:49
What are some of the other things you're working on in the lab today in terms of how the innate immune response works and anything related to this work?
Caetano Reis e Sousa 1:03:00
Yeah. So, I mean, we are continuing the work to try and understand how vitamin D modulates cancer immunity. But I mean, a lot of the core work at the moment in my lab has to do with understanding dendritic cells. I mean, we talked about dendritic cells as if they were one cell type, they are one white blood cell type, but they come in multiple flavors or subtypes, and no one fully understands what, whether they all do the same thing or slightly different things. So that's an area that we sort of focus on. Perhaps the area that I we're putting a lot of effort into is this understanding of cell death and how that translates into cancer immunity. I mean, that goes back to the very beginning of our discussion, when we were pointing out, when we were asking, how does the immune system detect the presence of cancer cells? And I was saying, one of the ways is by detecting death of cancer cells. I think this was something that had been postulated before but hadn't really been shown properly. I think we've now, over the years, been able to show that, and we tried to then understand whether, having shown it can, we now leverage that to make better immunotherapies. So actually, a couple of years ago, I spun out a biotech company called a dendro therapeutics that is effectively trying to make cancer cell death more immunogenic, if you will, ie, use our knowledge of how dendritic cells handle dead cells, dead cancer cells, to try and see if we can make the system more efficient. And even if we can persuade other cells, besides dendritic cells, to do the same thing, thereby increasing the number of sentinels that might be around in a cancer to alert the T cells against it. So we are doing quite a lot of work trying to develop biological agents that we believe might help with this, and you know, we'll have to wait and see if they turn out to be useful. But that is a sort of example of how what is effectively a purely academic project to try and understand how things work can nevertheless be leveraged, potentially to develop classes of therapeutics that weren't really envisaged before. So that's an area that's keeping us quite busy at the moment, and the final area that's keeping us quite busy at the moment is understanding how what the dendritic cell does when it takes up these bits of dead cells from a cancer, for example. And we discussed how these dendritic cells, put up bits of bacteria and present them to T cells. Well, they do exactly the same for cancer cells. They take up bits of the cancer cells or of the dying cancers or dead cancer cells, and present those bits thereof to T cells. Now, how cell biologically that happens turns out to be quite fascinating. It turns out that the dendritic cells take up these bits of dead cells into little vesicles that are inside them, and then they rupture those vesicles and disgorge the contents into the cytoplasm, which is something very unusual. So these are what are called endosomes, or phagosomes. And then ridic cells have a specialized mechanism where, in response to detection of these dead cell debris, the detection of the actin cytoskeleton, they actually actively signal to disrupt these structures and disgorge these contents for easier handling of the material for presentation to T cells. And that's a cell biological process that, to my knowledge, hadn't really been described before. We described it about three years ago, and so we are actively trying to understand how that is actually regulated, again, with the idea that not only it tells us something about biology and about cell biology in this case, but perhaps we can exploit it to make it more efficient.
Nick Jikomes 1:08:04
Is there anything that you'd like to reiterate for people from our discussion, or any final thoughts you want to leave people with before we sign off?
Caetano Reis e Sousa 1:08:14
I mean, I want to point out that the there's one important issue that has to do with vitamin D and supplements. This is just a cautionary note that I always like to leave people with all the work that we have done and all the data that we have in humans have to do with asking whether a deficiency in vitamin D is associated with particular outcomes, and correcting a deficiency seems sensible. In most cases, it does not follow that more vitamin D or more of any supplement will have additional benefits. In fact, it could have detrimental effects. So when people say, Should we take vitamin D, or should we take nutritional supplement X or Y, my general view on this, without being medically qualified and without wishing to give anyone any advice, but my view on this is, if you have a diagnosed deficiency in something that should be in your body, but is there at lower levels and then recommended, then, by all means, correcting that seems sensible, but do not assume that more of that thing will Give you a boost beyond what's normal. That's a fallacy, and it does not follow. It's not a logical conclusion. I, myself, being dark skinned, have been diagnosed as vitamin D deficient, and I do correct that deficiency by taking vitamin D supplements as recommended.
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