Short Summary: The science of cancer and immunity with Dr. Rahul Roychoudhuri, blending cutting-edge research with everyday implications like aspirin’s role in fighting tumor metastasis.
About the guest: Rahul Roychoudhuri, PhD is a Professor of Cancer Immunology and Immunotherapy at the University of Cambridge, where he studies how the immune system interacts with cancer to improve therapies. His research bridges basic science and clinical applications, focusing on immune responses to cancer development and spread.
Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Full transcript and other information on Substack.
Episode Summary: Nick Jikomes interviews Rahul Roychoudhuri on the immune system’s role in detecting and fighting cancer, particularly how cancer cells evade immunity through selection pressures and microenvironment manipulation. They explore cancer initiation via mutations and inflammation, metastasis mechanics, and a surprising link between low-dose aspirin and reduced cancer spread, spotlighting Roychoudhuri’s research on T cells and thromboxane. The discussion ties in dietary fats, aspirin’s anti-inflammatory and anti-clotting effects, and the potential for new immunotherapies to prevent metastasis.
Key Takeaways:
The immune system constantly surveils and eliminates early cancer cells, but surviving cancers evolve to dodge detection.
Inflammation can both spark cancer growth and be exploited by tumors to suppress helpful immune responses.
Cancer metastasis, responsible for ~90% of cancer deaths, involves cells breaking off, traveling, and adapting to new sites.
New research shows aspirin may curb metastasis by lowering thromboxane, a lipid-derived blood clotting factor.
Human data hints aspirin reduces metastasis risk in cancers like breast and colorectal, but trials are ongoing.
Daily low-dose aspirin (75-100 mg) is used for heart health, yet its cancer benefits need more study. 600 mg per day has been observed to reduce metastasis rates in colon cancer patients, but chronic use of that dose carries some risk (ulcers, bleeding).
Related episode:
M&M #200: Dietary Fats & Seed Oils in Inflammation, Colon Cancer & Chronic Disease | Tim Yeatman & Ganesh Halade
*Not medical advice.
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Episode transcript below.
Episode Chapters:
00:00:00 Intro
00:05:55 Cancer Immunosurveillance
00:11:56 Mouse Models & Selection Pressure
00:18:09 Tumor Microenvironment
00:25:43 Inflammation and Cancer
00:34:33 Immune Evasion Tactics
00:40:37 Aspirin Basics
00:48:01 Aspirin & Cancer Connection
00:56:23 Research on ARHGEF1 Gene
01:05:24 Aspirin’s Anti-Metastatic Effect
01:13:01 Lynch Syndrome & Aspirin
01:20:11 Clinical Trials & Metastasis Impact
01:22:48 Final Thoughts on Immunotherapy
Full AI-generated transcript below. Beware of typos & mistranslations!
Rahul Roychoudhuri 1:38
so I'm Raoul Roy Chowdhury. I'm the professor of cancer immunology and immunotherapy at the University of Cambridge, and we study the interaction of the immune system with cancer in the hope that we could better exploit its function in therapies.
Nick Jikomes 1:54
And, you know, I've done a few episodes that are cancer related, especially as they tie into metabolism. Obviously, I know what cancer is, but I'm not a cancer guy. I'm sort of a neuroscience and and endocrine guy. But I've gotten more interested in cancer as I've gotten more interested in metabolism, because there's so much fascination there, then obviously the immune system ties into this. Because as as many listeners will know, you know, we're getting cancerous essentially halt the time. Very frequently. I'm not actually sure what the background rate is, but normally a cancer cell arises, it somehow arises, and then the immune system handles it, it detects it, and it gets rid of it before it becomes a problem, before it becomes a tumor, and then, and then you learn about it, because you develop symptoms. So I want to start there with cancer detection and the immune system when cancer cells are arising initially in a healthy person, everything's working normally. What is the immune system doing to detect and handle that problem?
Rahul Roychoudhuri 2:49
Yeah, great, great question. So it really boils down to the fundamental relationship between the immune system and the transformed cell and the framework for understanding that interaction is the cancer immunosurveillance hypothesis, really, and that is that really cancer cells can be recognized quite potently by various components of the innate and the adaptive immune system. So, you know, early on, people wondered whether cancer can even recognize the immune system. Can even recognize cancer, because there were the observations that, for example, cancers develop an immuno competent host, right? We all have a functioning immune system, but can get cancer, and that cancer seems often not to be clear, unlike, let's say, an influenza infection, right, which is very apparent the immune system and rejected. But what we learned was that the this early assault from immunity, which, as you say, may clear these nascent cancer deposits as they're emerging constantly in our bodies, creates a strong selective pressure to a sort of Darwinian selective pressure for the growth of escape variant cancer cells that actually very good at escaping this mode of immune recognition and giving and so by the time cancer developed into something a person could say, feel or notice, they had the cancers actually undergone so much selection from the immune system that it's learned to become very resistant to immune attack, and so cancers grow at sort of the similar rates in immunodeficient and normal mice, for example, suggesting that actually well and the skeptics of cancer, immunosupveillance took this as evidence that actually immune system has nothing to do with cancer. But in fact, we now know that just that the cancers that emerge in immune intact hosts are different in their identity, they're different in their nature, they've learned to live with the immune system.
Nick Jikomes 4:58
Yeah, yeah. So. So a couple of things here, and this will be good, probably for the audience, that I'm not a cancer guy, so I'm gonna have to ask some basic questions here. I just sort of my understanding of this from a, literally a textbook perspective, because I took immunology 101, and that was basically my entire education in immunology. So that's the level I have. My understanding was, oh, well, of course, the immune system has to be involved in the initial phases of cancer because it just makes intuitive sense, right? You've got white blood cells that are surveilling the, you know, the parts of your body. They're on the lookout for things that shouldn't be there. We think of infected cells normally when we think of the immune system being activated. But of course, cancer cells make sense too. You call this the immunosurveilla surveillance hypothesis. To what extent is this a hypothesis? To what extent do we actually know that immune system plays a principal role in early detection of cancers generally?
Rahul Roychoudhuri 5:55
Ah, well, so, so we don't know as much about the early response to cancer, just because often cancers that that are emerging and have not grown into palpable lumps, that people have symptoms, we don't know they exist so that the cancer is less well understood. We know much more from mouse models, but it turns out that the relationship of different types of tumors is different. So for example, we know that there are cancers that arise from exposure to mutagens that create lots and lots of mutations to even protein coding genes within cells. When, when these when these cancers are grow into a small nascent deposit. Obviously these mutated self proteins start to look to the immune system, especially the adaptive immune system, as foreign just like the infected cell you you talked about, they have foreign proteins that T cells can recognize, and so these can be subject to adaptive immunity. But we also know that cancer cells can undergo a lot of stress, as this constant oncogenic pressure creates deranged metabolic processes within cancer cells, etc, and and sometimes those cancer cells start to expose stress ligands on their surface, and these can be detected by Cytotoxic cells called NK cells, or natural killer cells that can also attack cancer cells. So I think T cells and NK cells both lymphocytes with cytotoxic function, but either with adaptive or innate modes of recognition or play an important role in cancer rejection
Nick Jikomes 7:43
and in principle, like, what are some of the other ideas out there for how cancers initiate, if it isn't through some some work around of immune surveillance?
Rahul Roychoudhuri 7:56
Yeah. So, so well, so we know that mutagens, right DNA, mutagens, they can, they can certainly drive cancer by, for example, causing, by chance, the activation of oncogenic driver mutation or inactivating tumor suppressor genes. And cancer is a mutational disease. But we also know that inflammation can play a really important role in driving Yes, so we know this very clearly, for example, from mouse models. So we have mice with an APC min mutation, so that's an inactivation of a potent tumor suppressor gene, and these mice, just like individuals with familial adenomatous polyposis coli get colorectal polyps, which don't transition to cancer. If you now give the potent inflammation inducing agent Dexter and sodium sulfate to these mice, it's a callitogenic agent, they get colitis, and that colitis can provoke carcinogenesis. So suddenly, the APEC min mice get farming cancer.
Nick Jikomes 9:10
This, okay, so, so, a couple quick things there. So, so is the idea here, simply that you could have mutations to genes and or inflammation creating cancer, and the cancer cells unchecked, cell growth, cell division, is the idea that in some cases, at least a cancer can form and then eventually take hold, and the immune system might not be failing to recognize at any step. It's just the cancer is perhaps outpacing its ability to keep up before a tumor microenvironment can get initiated, etc.
Rahul Roychoudhuri 9:44
Well, I mean, you know, it's an interesting point about outpacing. I'm not sure we've actually studied that relationship very carefully. What we do know is cancer emerges from the process of this selection this early. Release electric immune system with the ability to fight off immunity. Perhaps the the experiments of Lloyd old and Bob Schreiber are the most important pieces of evidence for this, this hypothesis, and that is that you know, if you grow, uh, carcinogen driven tumors in mice, so this is through the injection of methyl cholanthrum into muscular tissue of mice, they develop fibrosarcomas. Now you can do that with wild type mice and rag deficient mice, rag one deficient mice, which lack T and B cell adaptive immunity. Cancers grow in both mouse you can then from the cancers that you dissect out from these animals, develop cancer cell lines that grew in a normal mouse or an immune deficient mouse, and you can now implant those cancer lines in new mice, for example, mice with a normal immune system or a deficient immune system. And what's striking is, while the cancers that grew within the presence of an intact immune system can grow both in normal and immunodeficient mice, the cancers that grew in an immunodeficient mouse can only grow in immunodeficient mice if you try to grow them in normal mice, the majority of tumors will grow to a certain size and then undergo complete remission. They will be attacked by the immune system, and they have no way of preventing that from happening. So it seems that this prolonged period when a mutagen driven cancer is just trying to grow beyond that initial few cells to establish a larger tumor escaping immunity. There is this strong selective pressure, a Darwinian evolutionary event, and you select cancer to evade immunity. And that property you can then characterize in such experiments I
Nick Jikomes 11:56
see. So if you basically, if you literally, put cancer into animals, into mice. One group of mice has a normal immune system. One group of mice has a deficient immune system. The ability of the subsequent cancer to grow in another mouse depends on whether it grew up, so to speak, in Yes, normal immune system mouse or deficient immune system mouse.
Rahul Roychoudhuri 12:19
I guess it's like, you know, if you grew up in a rough neighborhood, yeah, I guess the immune system being that rough neighborhood, then that cancer ends up being a little bit more able to survive life in a that similar rough neighborhood with you, if you put them
Nick Jikomes 12:35
in. And when we say selection pressure here, I want to you know, how far can we take the Darwinian interpretation here, as the cancer cells are initially arising in in these different mouse lines, as you described these experiments. Is there some, is there some kind of true selection there, where different versions of cancer cells are arising, and then there's, there's sort of a culling, and then a selection for very
Rahul Roychoudhuri 12:57
much so, so I you know cancer is a survival of the fittest process, simply by virtue of the mass of cancer cells, all individually, all initially derived from a single cancer cell. Subsequent to that, it's a very genetically and epigenetically unstable disease. So from that single cancer cell, you start to quickly get heterogeneity, and necessarily, some cells are fitter than others at surviving, yeah, as they continue to grow, they start to lose some of their characteristics that made them the cells of the tissue of their origin, and they become de differentiated even better at ground. You know, if you don't need to express all those melanocyte molecules associated with making melanin, why bother? You know, you could start to become a more efficient growth. And that applies also to immune selected pressure,
Nick Jikomes 13:55
yeah. And I would imagine, from the cancer cells perspective, it's a bit of a double edged sword, because the same processes which allow it to morph into something that's better at dividing might also destabilize it and make it more vulnerable in certain ways. Yeah,
Rahul Roychoudhuri 14:10
very much. So. So the most striking evidence for that is in mismatch repair defects. So obviously, when DNA is copied by ourselves, there are a bunch of proofreading enzymes that go on scuttle along after the polymerase and make sure all the base pairs have been written down correctly, and answers which destabilize mismatch repair can fuel that furnace of mutagenesis that enables cancer to become this heterogeneous, rapidly evolving mass. But what we've learned, especially in colorectal cancer, is that the susceptibility for colorectal cancer so immune checkpoint blockade therapy, therapy that works by invoking T cell assault of tumors, it works only in those colorectal cancers where. Repair where mismatch repair is defective. So cancers that are mismatch repair proficient, colorectal cancers are pretty Neo antigen sparse. They don't have many mutations that make those cells not seem like self. Whereas, when you have mismatch repair defects, there's lots of proteins with riddled with mutations that make T cells able to recognize them, and those are the ones that respond to immune checkpoint blockade
Nick Jikomes 15:26
I see. And so, so what I'm taking away from all of this is probably by its nature, and for all, or at least many, many cancers, there is so a there's a selection process that when the cancer starts, it's not the you know, you're not all things are not said and done. The cancer needs to grow into multiple cells, and then a subset of those cells, which are not all identical to each other, need to be selected. And the selection pressure here is for immune evasion, because almost, almost, by definition, the ones that can't immune system will simply be taken care of, will be, will be destroyed. And I would imagine that you know everything that you're telling us right now. This is a stochastic process, which would explain why a not all cancers take and be, why sometimes they just happen to there might not be, like it's a stochastic thing. I would imagine, yes, yeah,
Rahul Roychoudhuri 16:20
precisely, yeah. And what we're learning is that this kind of stochasticity may act not only during carcinogenesis, but also during metastasis, when cancers escape single cancer cells escape from their primary mass and establish a distant focus of disease elsewhere in the body, turns out that we're just beginning to learn that they face quite stringent immune surveillance, especially when you consider a cancer cell within a normal, large primary tumor has it is afforded protection from immunity now by a well established human micro environment that it walls off the immune system from attacking and killing those cancer cells. Remember, this thing has developed and has been selected to be immuno suppressive as an environment now, once a cancer cell sort of escapes and forms a distant locus, of and it's just a single cell in our in a distant tissue. Remember, it's in an immunologically primed individual. You know, it's been immunized with the cancer cells, as it were. It's divorced of that initial might suppressive micro environment. It's so enjoyed in its primary tumor. It's vulnerable. Yeah, it's highly vulnerable. And so there is this sort of window of opportunity where the immune system just nip it in the butt. Now it then takes months to years for that single cancer cell to arise a new metastatic deposit which has recreated that immunosuppressive microenvironment. So during that period, this long latent period, when just a tiny clump of cells or single cell is present in distant tissue. I do think there's this opportunity here to use the immune system to attack
Nick Jikomes 18:09
before we talk about that, I want to talk a little bit more about the tumor, micro environment. So if sort of a basic cartoon sketch here is one way or another, there's mutations, there's inflammation, something instigates the origination of cancer cells in the body. Those cancer cells start to divide and grow. And there's diversity there. There's some selection happening. They're initially adjacent to each other, but before they have set up a tumor, before a clump of cell my understanding of what a tumor would be, or how you might define it, actually, and I don't actually know the formal definition, I suppose, is there must be multiple cancer cells adjacent to one another. And they can't merely be adjacent to one another. They must have formed or be communicating in some way such that they're creating an environment that's now a unique environment. It's a cancer environment, whatever exactly that means that's no longer the normal host cellular environment. Well,
Rahul Roychoudhuri 19:07
you know, the cancer environment is, is a mass of cancer cells initially, but, but it's also, it becomes a sort of disordered tissue, like the Third Reich. And it's, you know, it's expansion into a disordered government. You know, in a way, cancer just doesn't build an orderly tissue structure with vessels supplying it. And, you know,
Nick Jikomes 19:31
eventually I would imagine these are, these are just like frenzied cells by nature. They're going,
Rahul Roychoudhuri 19:38
yeah, so they're going, going, going. They deplete metabolic resources from the environment in their competition against themselves. We now understand that that metabolic competition also impinges upon effective immunity against cancer. So, you know, cancers, for example, rob the. Met the environment of glucose, and we know that T cells need glucose to activate, so that's a very straightforward way in which they suppress immunity. But finally, you know they are hypoxic, and that hypoxia drives necrosis at the core. So there's lots of cell death happening within the cancer, but you do get some vascular Genesis, so some new vessel formation. And you know, they release veg F and other mediators to try and achieve this. They can recruit immune cells like macrophages to help. But yes, they're a very disorderly environment too. So
Nick Jikomes 20:40
it almost sounds like, if I imagine a large or mature tumor, it's such a frenzied environment that it's sort of rotting from the inside out. The center of this thing is probably literally necrotic, rotten cells, and then the periphery is, you know, able to, actually, you know, be fertile in some sense, yeah,
Rahul Roychoudhuri 20:58
yeah. Indeed, yeah. So great, yes, and that's one way of looking at it. And this necrosis, you know, people would refer to immunogenic cell death, because when cells apoptos, they sort of do this orderly clearing up of their proteins and DNA in a relatively non immunogenic way. But when cells just Necros, when they've just run out of energy. They can't stably maintain their volume. Everything just explodes. And all those intracellular sort of proteins, DNA, just spill out extracellularly. And that can tell cells of the innate immune system, dendritic cells, that there's stuff going on here. Is damage happening. And then dendritic cells, their job is to take up necrotic debris from the outside space process and present what they've taken up and present that to the T cell system in lymph nodes. So that's where the initial immune response to the cancer will start, in the lymph node, where the meeting place of all these naive T cells with all their various receptors against various potentially foreign antigens. And so, you know, what you need is a bit of necrosis to incite that.
Nick Jikomes 22:12
I want to ask you some broad questions before we dive into the paper and stuff. So we're going to be talking about a familiar drug to many people, aspirin, which is a well known, well, well known drug anti inflammatory. I want to ask you a little bit more about inflammation and the origins of cancer. You've mentioned inflammation. You've mentioned colon cancer models. I had Tim yaitman and his colleague, Professor Halliday, on recently. I'm not sure if you're familiar with this work, but we talked about colon cancer and Omega six polyunsaturated fatty acids, the things that are in a lot of the processed foods that are out there, like seed oils and long story short, they basically showed, I think, fairly well, that using lipidomics, the basically this colon cancer has to do with the creation of hyper or an excessively inflammatory micro environment. What do we know in general about the instigation of excess information and how it relates to things like fatty acids that can then facilitate cancer?
Rahul Roychoudhuri 23:19
Wow. Well, that's somewhat outside of my scope of understanding. So, you know, I think there are many sources of inflammation, and we know that cancers can attempt to provoke the wrong kind of inflammation to perpetuate some of the characteristics of the tumor that cancer cells want. We know that you know. So some people say there is tumor initiation by mutations, but tumor promotion by inflammation. And so those with background levels of inflammation, whether it be through diet or and even an adaptive immune process, you know, maybe at greater risk of certain cancer types.
Nick Jikomes 24:04
And I think, but maybe one core thing to get to people here is there are many different inflammation. Is not one thing. There are many different forms of inflammation, many different mechanisms, many different pathways. And it sounds like, to some extent, we know, that the cancers can play up or play down different pathways to
Rahul Roychoudhuri 24:23
they spend a long time curating which type of information is driven. You know, we know that, for example, type two immunity is quite suppressive to the antiviral sort of type one immunity that we now know plays an important role in also recognizing cancer, where viruses lurk inside cells. So the kinds of immunity you need to detect things that inside your cells and then get rid of them inside your cells by killing the cell itself. That's the same sort of immunity that attacks cancer, right? Cancers lives within ourselves. It is our cells, so you know. And then you have type two immunity. That's. Better suited for, you know, anti parasitic responses, very much an extracellular threat. And part of dealing with a chronic parasitic infection is to rebuild the tissue, to regenerate it, to promote its sort of proliferation, almost at the epithelial surfaces. What tumors like about that is it's producing growth factors that drive tissue remodeling and proliferation, and it that, you know, the immune system, the adapts to try and focus its efforts so often during a anti parasitic response, the whole system is skewed towards that response, type response,
Nick Jikomes 25:37
so there's regeneration. You're essentially inadvertently giving the cancer fertilizer. Yeah, exactly.
Rahul Roychoudhuri 25:43
So the cancer spends a lot of time curating the environment so that it becomes in in Clemente, antiviral response and growth promoting.
Nick Jikomes 25:55
So, okay, eventually that progression,
Rahul Roychoudhuri 25:57
we talked about carcinogenesis, the role of inflammation, carcinogens, and then the wrong kind of inflammation also promotes cancer after the
Nick Jikomes 26:05
Okay, so, so inflammation can be good or bad to a given tumor. Oh, yeah, yeah. And so before we dive into some of your specific recent work, so after a tumor has formed, I want to give people a sense for how the tumors the core ways that tumors sustain themselves. So we've talked a little bit about how they are able to tune up or tune down inflammation in different ways. What are some of the other hallmarks of how tumor microenvironments get established? Here I'm thinking about metabolic rewiring and things like vascularization. How are they actually able to recruit and remodel the tissue environment around themselves to facilitate tumor growth. So
Rahul Roychoudhuri 26:45
cancer cells have to So cancers arise from mutations, of course, but as you know, in our bodies, you know, all the cells in our bodies have the same genetics, but very different phenotypes, see through eye cells, beating heart muscles, all from the same genetics. So it's not just mutations. We know that the epigenetic identity of cancer is very different. So suddenly, you know, cancers don't just have to mutate, break something or considerably activate a gene. They can down regulate proteins or up regulate proteins that the normal tissue they came from didn't have access to because they were epigenetically locked away. Suddenly, cancer can utilize all the genes in the entire genome at its will. You know, it can up regulate and down regulate different genes to create the right phenotype. And by doing so, you know, they can up regulate TGF, beta, they can up regulate veg F, they can curate the micro environment. So it's Clement to cancer growth. And so our initial concept of cancer, I guess, the original hallmarks of cancer, really did focus on the cell intrinsic things like, you know, if escape from the need for growth factors, right? So mutations in pathways which growth factors activate? Well, if you just consider reactivate pathway, you no longer need the growth factor. That's the sort of basis for cancer escape from tumor suppression, tumor suppressor genes, you know that. You know, loss of cellular senescence, all these cell intrinsic changes. But then, you know, we now have this emerging understanding where really immune suppression, the creation of new vessels, the invasion beyond tissue boundaries in a, you know, which requires matrix remodeling. All these cell extrinsic processes now come to the fore as as our understanding of cancer develops, beyond that sort of understanding of the cell intrinsic changes.
Nick Jikomes 28:55
There may be many answers to this, there's, there's, I would assume, certainly not like one answer. But when we think of, I don't know, quintessential cancers, or maybe the most common cancers, and we're thinking about the tumor, this immunosuppressive environment gets created where, where somehow the immune system is being thwarted in different ways. Are there any basic like principles there for how that's normally done is, is the outside of the tumor sort of camouflaged so it's not recognized as a tumor. Are is the tumor microenvironment such that it sort of kills immune cells if they go inside of it. How is it actually like getting around the immune system?
Rahul Roychoudhuri 29:31
Oh, there are so many mechanisms. I mean, the early descriptions of cancer in, you know, editing that that that sort of experiment, where this cancer cell that grew in the non immune environment couldn't grow in an immune environment. The ways the cancer cells emerged that could grow in immune environment often involved what's called antigen loss, variation. So remember that the adaptive immune system and T cells, they recognize cancer. Is because they have mutations in certain normal proteins. They don't have to be cancer driving mutations. They can be what's called passenger mutations, just random transition mutations. They make foreignness out
Nick Jikomes 30:11
of self something doesn't look right, yeah, yeah. Something doesn't
Rahul Roychoudhuri 30:15
look right. That creates an antigen for T cells to specifically recognize. Now, what the cancer cell can do is many things it can either you know. So these antigens for T cells are peptides derived from your normal proteins. They're loaded in a molecule on the surface called MHC. Now, the loading requires certain amino acids at different places to be loaded in MHC to be presented to T cells. And so what you what cancer cell can do is is break one of those amino acids, preventing the loading of that antigen and presentation to T cells, or it can down regulate the protein containing this new Neo antigen that's made it such a target, if it's not a if it's a dispensable protein, especially just be down regulated or a stop codon earlier on in that protein will prevent the translation of the foreign protein sequence. So there's lots of ways antigen can be lost. Now we talked about MHC molecules being key to presenting antigens to T cells, which then attack the cancer. Well, you know, one can have down regulation of MHC so that less foreign peptides are being presented to T cells. Now that renders, I mean the immune that would be such a useful way of escaping all of adaptive immunity that the immune system has other components, like NK cells, natural killer cells that can specifically recognize cells that have down regulated MHC. So what cancers do is often just down regulate it a notch. They can't lose MHC entirely without being assaulted by NK cells. As a consequence. I see,
Nick Jikomes 31:50
I see, so, so yeah, if you, if you try to hide, too clever, cleverly, that's itself a marker that something's wrong. Oh yeah. So the cancers are pretty can be subtle in how they do this. Oh yes,
Rahul Roychoudhuri 32:00
and that's where epigenetics comes in, right? So you well or copy number loss. You can get copy number loss, but you can also get epigenetic down regulation of MHC, not so much mutations in it, epigenetics, yes,
Nick Jikomes 32:13
there's just less of it. It's not, doesn't look funny, yeah, not
Rahul Roychoudhuri 32:17
as you're not funny enough to get NK cells all click side, and then you've got, you know, co option of a variety of cells that exist in the immune system to keep the peace. Remember, the immune system is like a big standing army. It's ready to attack foreign foes, you know, infections. It can even attack cancer, of course. But that standing army can also wage war against yourself. In autoimmunity, it can cause collateral damage in immuno pathology during an infection, or it can cause allergy, a reaction against normal foreign substances that you don't want, you know, innocuous foreign substances you don't really want to attack. So we have lots and lots of fail safes, which stop aberrant immune activation. These call immuno regulatory mechanisms, and some of these have some of these mechanisms depend upon cell types within the immune system with dedicated immuno regulatory function, such as regulatory T cells, says it on their name, but also myeloid derived suppressor cells, for example, and these cells have the license to switch off immune responses. Now, cancers are derived from self tissue, so they have some license to be protected by these cells, but they learn to co opt this protection and secrete all the right things to enable those cells to come into the tumor and find a really stable home there. So we can find lots of regulatory T cells packed full of tumors are packed full of regulatory T cells suppressing useful immune
Nick Jikomes 33:55
and so based on everything that you've told me so far, in terms of the selection process by which the cancer cell that ends up really becoming the problem makes it to that point by which the cancer cells learn to learn to tune their gene expression in often subtle ways, all of this stuff. Even if you have two people with what you would otherwise consider to be the same type of cancer, they both have breast cancer, they both have a mutation in the same gene. It's each one is going to be unique to the individual, because it's going to be each cancer cell line per person will be tuning itself to that local environment. So there's probably never truly two identical cancers very
Rahul Roychoudhuri 34:33
much. So there's some stochasticity in, you know, shape. It doesn't have to just be a response to the environment. There's certainly stock assist in what mutations happened, in what other genes to make cancer how it is. So cancer is, of course, a genetically heterogeneous disease, but also probably an epigenetically heterogeneous disease. What has been a common unifier, though? How? Been the general interaction between the immune system and cancer. So this success of checkpoint immunotherapy, which really has had cross cutting therapeutic efficacy across a variety of cancer types, departed us from, you know this, this trajectory in oncology towards personalized medicine, really highly personalizing the medical approach, depending on exactly which mutations that cancer had, and giving selective, targeted chemotherapies for that, we now understand that the immune system's relationship with cancer, that T cells can recognize cancer and kill them and they're suppressed by common factors meant that we could develop therapies effective across a variety, not all cancers, but a variety of cancers that are effective. So it's been a great level of that heterogeneity. In ways, all infectious agents are somewhat different, but the modes by which we can vaccinate against them are somewhat similar. Yeah,
Nick Jikomes 35:59
yeah. So, they're all unique, in some sense, and there's going to be certainly a place for personalizing things, but there are more general patterns, and there probably are more general approaches, thankfully, that would enable treatments that maybe we'll come to that either help on the prevention or the treatment side once cancer arrives, absolutely, I Want to talk about metastasis a little bit. Can you just define in basic terms what metastasis is for people, and general principles we know about how or why it actually happens?
Rahul Roychoudhuri 36:30
Yeah, sure. So cancer, metastasis is a very simple concept. So cancer starts as a localized disease, a single cell that grew into a patch of cancer cells that becomes the primary tumor when that primary tumor often grows in places where the patient doesn't really know it's growing. Yet, some cancer cells can escape away and travel via blood or lymphatics to distant tissues. Sometimes it's just via the lymphatics which drains all tissues to its local draining lymph node. But it can also go beyond that and spread to other sites, commonly the lungs, the bones, the brain and these and this process really transforms a localized disease which can be treated with curative potential with surgery, we just cut out every last bit of cancer into a widespread disease that's now extends beyond the scope of curative surgery. Right? When you have multiple nodules of metastatic disease, probably even more micro metastases that haven't fully grown up yet, you can't go and cut every single one out. And that's where the terrible survival outcomes from cancer come from it's in the metastatic context, and so it's the 90 the cause of 90% of cancer deaths is metastasis.
Nick Jikomes 37:52
And I guess to what extent, just to put it broadly, to what extent is this sort of a random, stochastic things, basically a clump breaks off somehow, versus a regulated process that the cancer cell sort of purposefully instigated, yeah, I mean
Rahul Roychoudhuri 38:13
applying sort of teleological principles that cancer wanted to do things. I mean, well, we apply telelogic principles to people, but we're also products of evolution. I don't know there is a selective pressure for metastasis.
Nick Jikomes 38:30
Is it random, or can it be predictable? Are there conditions in which the probability of metastasis goes up for some well known reason? Okay,
Rahul Roychoudhuri 38:38
well, I think cancers obviously invade normal tissue boundaries and the proximity to vasculature, and perhaps even the derangement of vasculature may have something to do with it. We know that metastasis requires metalloproteinases which enable invasion beyond tissue boundaries, the extent of lymphatic drainage could be, could help metastasis. We know some cancers metastasize more than others, but yeah, there, there are many processes that and many steps in the process of metas. So cancer has to get close enough to a lymphatic vessel or a blood vessel to be able to get into it. It doesn't just fall out. It has to go through the vessel wall, so great, out into the into survive the sheer stresses of traveling at high speed relative to a single cell. Yeah, in this, in this blood flow and, and, you know, some people say the the site when, when eventually the cancer cell gets lodged in a capillary bed, is a bit like a crash site. Many cancers will just. Die from sheer stress. Oh,
Nick Jikomes 40:01
wow. Okay, so by their nature, right? They're dividing. They're invading. If they start to push up against a new tissue type, they're probably going to get in there if and when they can, if, if, you know, things happen that way. But then they've got a new challenge, which is they're in a new environment. They might even get literally shot through the bloodstream and crash into a wall. And so on the one hand, there is the casticity there, but on the other hand, I mean, this is their nature to grow and invade. So part, part of it could just be like, are they pushing up against a blood vessel or something, that
Rahul Roychoudhuri 40:32
kind of thing, I think interesting.
Nick Jikomes 40:37
So let's talk about aspirin now, before we unpack this paper, everyone knows. I mean, everyone probably has aspirin in their cupboard. Everyone might know that it's an anti inflammatory. But what is aspirin? How does it work? What do we actually know about
Rahul Roychoudhuri 40:51
it? So, yeah, so aspirin is an irreversible inhibitor of cyclooxygenase enzymes. These enzymes play a critical role in the breakdown of arachidonic acid pathway metabolites, and those can be used by various cells to make little molecular messengers, which have loads of roles in inflammation, but also clotting. So these prosthenoids that are produced downstream of the breakdown of membrane lipids, so that this whole system, the arachidonic acid pathway system, involves the breakdown of lipids and processing of those lipid breakdown products into a whole class of molecular mediators called prostanos. One of the most notable members of this family are prostaglandins, right? So this is why you take, you would have taken high dose aspirin if you had a fever or swelling, and why we all take ibuprofen when we have, you know, a fever an infection is to bring down the inflammation. We do so by reducing the levels of prostaglandin
Nick Jikomes 42:12
so these are inhibiting enzymes that are involved in the creation of those prostaglandins.
Rahul Roychoudhuri 42:17
Yes, and downstream of the academic pathway, metabolites are also thromboxanes, and these play a role in a completely different system, the clotting system. So we know that platelets have cycloalcinas, and they utilize the breakdown product of membranes as well, but they make thromboxane, and that's a potent plotting factor. In fact, the reason we take aspirin at low doses daily, some people, is to prevent the clotting of blood and the and thereby prevent heart attacks and strokes that can happen with inappropriate clots.
Nick Jikomes 43:00
Yeah, there's a lot potentially to unpack here, but you know, to reiterate some of what you said for people, non steroidal, anti inflammatory, drugs like aspirin are inhibiting parts of the machinery that takes you from certain lipids to lipid based mediators of inflammation and clotting, things like the prostaglandins and the thromboxanes, right? And so these things come from something called arachidonic acid, and this is itself coming from polyunsaturated fatty acids that we ultimately get from the diet. Is that,
Rahul Roychoudhuri 43:38
right? Well, yes, yes, eventually Yes. So
Nick Jikomes 43:41
okay, so this is a whole sort of lipid based inflammation system. Yeah. These are fatty, fatty molecules, yeah. Okay, so aspirin inhibits Cox, one co x1, that's one of the key enzymes in in this sort of picture. And and this is just a normal part of of how the body regulates inflammation through some forms of information come from these lipid based things, yeah,
Rahul Roychoudhuri 44:06
yeah, and clotting. So in these two aspects to the the function of tox inhibitors, they can prevent clotting. They can prevent inflammation. But what's intriguing about aspirin when taken at low doses, yeah, is aspirin has a remarkably short half life, so its effect on both Cox one and Cox two, so there's two cyclooxy its effect on cyclooxynas is irreversible, so once aspirin has irreversibly acetylated its target proteins, they're out of action. But aspirin only lasts around in the in the bloodstream for a half life of 15 minutes. So it's constantly having in concentration and 15 minutes, half the concentration by 30 minutes. Okay,
Nick Jikomes 44:55
so does it short acting? But it's a very effective at what it does.
Rahul Roychoudhuri 44:59
Yeah. Yeah. So it's very short acting. It lives around for a very short period of time. However, the target molecule for the inflammatory context, Cox two, is expressed by nucleated cells, because they have a nucleus. They can make messenger RNA. They keep renewing their pool of Cox two all the time. Cox two has a very short half life. And so it's thought that once daily, low dose of aspirin, very little effect the the inflammatory Cox two pathway, because Cox two is constantly being replenished, though, when you first give it, Cox two will be irreversibly inhibited. Yeah, that rule of irreversibly inhibited enzyme is replaced by
Nick Jikomes 45:43
and when people, you know, I've heard a lot about this in different contexts, when people take low dose daily aspirin or something close to that. Can you give us a sense of a, what is low dose for an adult, say, and B, what types of people are taking aspirin daily, or are commonly advised to by physicians.
Rahul Roychoudhuri 46:04
So a low dose of aspirin that the exact dose differs in different countries. In the UK, it's 75 milligrams, because that's sort of tablets you get over here in the US, it's 82 Yeah, yeah. So it's anything sort of, really below about 100 milligrams, yeah, that would
Nick Jikomes 46:21
be considered basically low dose, low dose aspirin. And
Rahul Roychoudhuri 46:25
people get prescribed aspirin to prevent thrombosis, basically inappropriate clotting of blood, and that can happen in people with certain atherosclerotic processes. So people with heart disease at risk of getting strokes or getting heart attacks might be asked to take daily low dose aspirin to prevent the propensity of their blood to clot. People with certain heart dysrhythmias, for example, if they have atrial fibrillation, used to be put on daily low dose aspirin. So it's really to stop clotting. Yeah, it's not really to target inflammation. If you need to, if you have a fever and you need to take aspirin for it, you'd have to take a milligram four times a day. Yeah, something there about so, you know, you'd have to take a huge, hugely greater dose, much more frequently.
Nick Jikomes 47:28
Yeah, yeah. So there's, there's multiple things downstream of arachidonic acid. Aspirin fits into this picture, but it's really the thromboxanes, the things that are involved in clotting that people get prescribed daily Lotus. So when, basically what you're saying is when people have or might have or be at risk for heart issues, cardiovascular issues, they those types of people will often get prescribed, or recommended by a physician, low dose aspirin because it has this inhibitory effect on the creation of these clotting factors called thromboxanes.
Rahul Roychoudhuri 48:01
Yeah, that's
Nick Jikomes 48:01
exactly right. Okay, so you did this paper recently that was really intriguing. Yeah, so we're talking about aspirin, we're talking about clotting, we're talking about inflammation. You wouldn't necessarily, naively, you would think that aspirin would tie into cancer, but, but you've got the story that's emerged. Can you walk us through the beginning of this?
Rahul Roychoudhuri 48:22
Yeah, I mean, perhaps I should explain the context a little bit before for what we did, because we didn't know much about aspirin when we got started here. So, but we've now become aware that there is quite a literature around aspirin and cancer. For example, we have known for some time that people who take aspirin. So there were large clinical trials done, prospective, randomized, controlled clinical trials were performed to establish some of the tenants I told you about, about aspirin preventing clotting of various consequences of thrombosis, right? So these were stat these principles were established through large randomized control studies with placebo or daily low dose aspirin or such. And what happened was an emeritus epidemiologist, Peter Rothwell, went back and looked at those patients who received the aspirin or control and asked, was there a difference in cancer incidence, and was there a difference in cancer recurrence in those large populations treated with aspirin, Oculus or control and what he found was actually that in those patients who were unfortunate enough to be diagnosed with a cancer, the chances of that cancer being a metastatic cancer at the time of diagnosis was let. Less and substantially less, 30, 40% less, if that patient was taken aspirin, if
Nick Jikomes 50:05
they just happen to be taking it, maybe because they had
Rahul Roychoudhuri 50:09
a card they were taking it, because they were randomized to take it on clinicals. Oh, I'm sorry, yes, this is yeah, sorry, yeah. This was retrospective analyzes of formal, randomized control studies. Oh, wow, okay. But the end point of those studies was not cancer, but the records were made. So, you know, you could
Nick Jikomes 50:26
I see, okay, so the purpose wasn't to check for this effect, but, but, but they were diligent in what they were taking notes on. Basically, yeah,
Rahul Roychoudhuri 50:32
wow. So this was a retrospective analysis, so it wasn't the primary sort of what the study was looking for, if you will. And they also looked at the chances that people without metastasis at the time of diagnosis, what their chances of getting a recurrence in dying from it were. And that was also substantially reduced by aspirin treatment, 40, 50% reduction in the rate that people without cancer, metastatic cancer at time of cancer diagnosis died from cancer was substantially reduced in patients taking aspirin. That's some of the context. Some meta analyzes have managed to reproduce these observations using different cohorts of people treated with aspirin.
Nick Jikomes 51:19
Okay, so there's there were some pretty good hints out there that something was going
Rahul Roychoudhuri 51:22
there was some good hints, but I must also say that there was some contradictory evidence. There was a prospective randomized control study of aspirin taken every other day in elderly individuals above the age of 70, and in that study, no effect on cancer incidence or or or death was noted. So you know, if anything, there was even slightly greater risk of of cancer death. So there is contradictory evidence in the literature, but there was this really intriguing signal that has formed the basis for prospective, randomized control studies to look at the effect of aspirin on cancer metastasis in people with early cancer, without metastasis, treated at the time of diagnosis.
Nick Jikomes 52:09
Okay, so, so did you guys? So did you guys. You got you saw those signals in the literature, and then did you go in with the intention of looking at aspirin here? Or did you sort of go back and discover these? Yeah, was it the other way? Yeah. I
Rahul Roychoudhuri 52:20
wish it was the way, but as with many scientific stories and sets of findings, we completely chanced upon this interest in aspirin and indeed, in prosthenoids. So we we've been interested for a while in whether this vulnerable moment of cancer development, where cancer cells are metastasizing in distant tissues, when that cancer cell is a single cell in a distant tissue, latent, but the cause of recurrence is that cancer distinctly susceptible to immune attack. And can we use that to create new therapies with dedicated anti metastatic function, that was the idea. And so to understand the mechanisms of host immunity to cancer metastasis, we turn to this beautiful but extremely laborious study done by David Adams and his wife, Louise Van der waiden, just down the road at the Sanger Wellcome Trust Sanger Institute. What they'd done is they'd used about 1000 initially, 810 they've expanded this study mice that were knocked out for individual genes. So we they had access to mice in which different single genes had been knocked out in host tissues, and they subjected each of these mouse strains to the metastasis assay of injecting melanoma cells directly into the tail vein of the mouse and counting them on Mets that grow in the lung 14 days later. This isn't very painful or harmful to the mice. They're just little nodules that grow in the lung that can be counted after euthanizing the animal 14 days after injection. And they wanted to look at agnostic to the genes that were just focusing on genes with relatively uncharacterized function at whether any genes, when lost, not in the cancer cell, but in the host, could either increase or reduce metastasis frequency. And the remarkable thing was, most genes had no effect on cancer metastasis rate, but there was a handful of about 15 genes in their first study whose deletion in host tissues resulted in a decrease in counter metastasis frequency. And we started asking whether there was, you know, material there, whether there was sort of a subject there right for study. So we looked through those 15 genes, and some of those stood out as potential immune regulators. And so we went for understanding what one of those genes, A, R, H, GEF, one does, and
Nick Jikomes 54:56
what, what. Stood out about that gene. What does it do?
Rahul Roychoudhuri 55:03
So? Well, we know that it's a signaling molecule that receives signals from a class of receptors called G protein coupled receptors. These G protein coupled receptors are seven membrane spanning block nest monsters, but there are loads of these receptors, and they signal through specific intracellular signaling cascades, not kinase pathways the phosphorylation system, but rather G protein signaling pathways. And so there are a variety of these adapter proteins, these Arh, geth, these guanine exchange factors that receive signals from receptors outside, and they transduced those signals to some form of cellular change on the inside. And that was kind of what was known with air HF one, that it's a it's a guanine exchange factor for G protein coupled receptors coupled to either GL for 12 or GL for 13 G proteins, and they cause variety of downstream signaling events.
Nick Jikomes 56:04
So it's a signal transduction molecule. It's involved in the detecting thing, the process of detecting things on the outside of the cell and transducing that, or changing it into a signal that changes stuff on the inside of the cell so that I can respond
Rahul Roychoudhuri 56:15
yes, and very little was known about its immune function, especially in the context of cancer
Nick Jikomes 56:23
and so, so, so what happens next in the story? So
Rahul Roychoudhuri 56:27
we thought, okay, well, this is a relatively novel gene to have an anti metastatic effect. Maybe we can make this into a study, right? We need to know that there's enough novel space around this for there to be something to publish at the end. So we got these knockout mice and characterized. Just wanted to make sure the results of this screen held up, because screens are large studies perform parallel there can be false positives quite reasonably in screens. So we got these mice and made knockout and wild type mice and could recapitulate this profound anti metastatic effect across a variety of different cancer models. We had germline cancer, breast cancer model where mice develop a breast cancer that then spontaneously metastasis the lung. We saw an effect of deletion of Erich geth one there in liver metastasis, model and several lung metastasis models. So
Nick Jikomes 57:25
you saw it across several types of cancer. And I would imagine that's very important thing, especially if you're interested in, or you eventually want to come to something like, you know, a general protocol or general possible treatment, as opposed to something that needs to be super, super specific to water. Yeah. So
Rahul Roychoudhuri 57:41
that's one thing the immunologists, I think, have brought to cancer biology, is this interest in broadening scope rather than focusing in on a particular molecular pathology.
Nick Jikomes 57:53
And then how do you eventually hear? How does aspirin eventually enter this story? So you identify this gene, this important?
Rahul Roychoudhuri 57:59
You know, it's loss in all tissues, results in this Aztec effect. Now, what we were able to show is, if you get the bone marrow stem cells from Erich, get one deficient mice and reconstitute a normal mouse's immune system. With those bone marrow stem cells, you can also confer the metastasis resistance phenotype. So that told us it was within the blood forming or hematopoietic system that this thing is happening. And that led us to ask whether there was an immune dependency of its action.
Nick Jikomes 58:31
I see. So the basic name, so just for people to follow, the basic logic here is, you're reading the literature. You're literally reading stuff. And you noticed this interesting study. You notice that had a set of genes where they had made some interesting observations. You guys then saw one gene that seemed very interesting. You knocked it out in every cell of the mouse body, and you saw that it had this interesting effect on cancer metastasis, reduced metastasis frequency. And then you made a more specific mouse genetically that only lost that gene in its bone marrow, where immune certain cells are made, and you could actually reconstitute other mice with that. So you could literally put that one gene deficient bone marrow essentially into otherwise completely normal mouse. And you saw basically the same overall,
Rahul Roychoudhuri 59:15
exactly. So this was just homing in on where this gene deletion might be having this effect, and it seemed to be in the immune or the blood forming system. And so we then made a new mouse strain, enabling us to specifically delete the gene, but only in specific cell types in the mouse, to really clinch
Nick Jikomes 59:37
it. So now you're going to one cell type at a time, yes. So
Rahul Roychoudhuri 59:40
we can now use conditional genetics to essentially have a mouse with an intact air of Chef one gene, except in a specific tissue. And in this case, we looked at NK cells, natural killer cells, which we've talked about macrophages, and finally, T cells, and it was the T cell specific deletion of the. Gene that resulted in the same reduction in metastasis rate
Nick Jikomes 1:00:04
and which, which type of T cells are these.
Rahul Roychoudhuri 1:00:07
So they are all T cells, all T cells, okay, traditional system, which removes the gene in all T cells, CD four and CD 8t cells.
Nick Jikomes 1:00:17
And so this would include, so basically, when we say T cells, this would include white blood cells that can sort of recognize foreign antigens on the surface of a cell, or those that make antibodies.
Rahul Roychoudhuri 1:00:29
They are the cells that can recognize foreign proteins expressed within cells of your own body, and they tend to then make cytokines that can arouse the immune system, or they can actually kill your own cells when they might express something foreign inside.
Nick Jikomes 1:00:51
Okay, and so the T cells are important here. It's really starting to make sense why you would see the type of phenotype that you saw. What happens next? So
Rahul Roychoudhuri 1:01:02
I thought, wow. So we spent a while characterizing this T cell knockout of Aries KEF one. We could see this anti metastatic phenotype. This was associated with heightened T cell activation within mice bearing metastases in their lung. And I thought, well, this is, this is a story. I mean, we didn't know this before. We didn't know it was a T cell specific phenotype, G, the first autoropa. But, you know, it's time to publish your work. You know, you've spent three and a half four years on this, but he was very interested in this kind of beginning of the lockdown, very interested in understanding what's activating this signaling process. And I was like, it's going to be a, you
Nick Jikomes 1:01:46
know, who knows Wild
Rahul Roychoudhuri 1:01:48
Goose just so, yeah. So what we ended up doing was looking up what in a previously published work, which G protein coupled receptors, those receptors on the surface that this guanine chain factor actually transduces signals from which of these receptors are expressed on T cells, such that we could then get the known things they receive sent signals from the known ligands of those receptors, and then screen, do a Little in vitro screen to understand which of these signals for which of these receptors is actually activating EHR. Sketch one to achieve this suppression of T cells. And this is where we discovered that thromboxane, a two this potent plotting factor downstream of the acrylonic acid pathway, metabolites suppressed by aspirin when you place a stabilized form of thromboxane a two on T cells, it potently suppresses their activation and proliferation. But when you knock out air HF one in those T cells, thrombox a two has no impact on the T cell whatsoever. So it's a very specific signaling mechanism that takes thromboxane a two and it causes that to suppress T cells and activation proliferation. And when you get rid of it, you lose that if, and that's what we found in vitro.
Nick Jikomes 1:03:15
And so how does aspirin tie into that? I mean, I can sort of imagine it now that you've mentioned the thromboxanes, but let's split
Rahul Roychoudhuri 1:03:21
up for people. So we now made this finding in vitro that thromboxane is this hitherto relatively unappreciated regulator of T cell immunity, and it does so via this, you know, unappreciated signaling intermediate air, HF one, but we want to map whether this anti metastatic effect was somehow being activated by thrombox N A two in vivo, right? So we started to think, Gosh, what? How could we change the levels of thrombox N A two in vivo and see whether this so the first thing we did was just give a stabilized form thrombox a two to mice and then give them the metastasis model I talked about. And indeed, when you give thromboxane a two to mice, you see, and this isn't the first time this has been observed, you do see an increase in the metastasis frequency. So thromboxane two can drive metastasis sometimes.
Nick Jikomes 1:04:16
So this thromboxane is sufficient to increase metastasis. Yeah. Yeah,
Rahul Roychoudhuri 1:04:21
exactly. And then we thought, well, let's do the reverse. Let's reduce the amount of thrombox atrium. We'd read a paper where aspirin can reduce metastasis frequency, not only in in these clinical retrospective studies, but also in mouse models with the same model of metastasis we were using. So, you know, a lot of science, you want established protocols, because there's a lot that would need working on if you don't use established protocols, this paper showed that aspirin has an anti metastatic effect. You can give thromboxane back and reverse the anti metastatic effect. So we use the same protocol, but we found that if we did this, when we gave. Normal mice, aspirin, we reduce the rate of metastasis. If you give back thrombox na two, you can recover the number of metastases, showing that effects seem to be mediated by throx N A two removal. But then, when you did this on mice with a T cell specific deletion of airs get f1 there was no change caused by aspirin or thrombox N, a two in the frequency of metastasis
Nick Jikomes 1:05:24
I see. So the T cells need to be able to respond to thromboxane in order for this to happen.
Rahul Roychoudhuri 1:05:31
Yes, so that there's function to be suppressed in the context. So if you
Nick Jikomes 1:05:35
give an animal thromboxane, this arachidonic acid clotting related factor, it increases metastasis. Aspirin inhibits enzymes that end up making thromboxane in the end. And so by giving aspirin you're you're essentially taking down thromboxane levels and thereby inhibiting metastasis, which would otherwise be promoted by thromboxane.
Rahul Roychoudhuri 1:05:57
Yes, precisely. And all of that has to do with the teeth findings, yes. And what the findings suggested was, this was, in our model, a T cell dependent process, and
Nick Jikomes 1:06:08
forgive me if you mentioned this. So this, this effect of aspirin, is this seen in multiple types of cancer.
Rahul Roychoudhuri 1:06:16
So we did not test the aspirin effect in multiple types of cancer. By this stage, in the paper, we were focusing continuously on using the same metastasis model, intriguingly, that model of cancer, the B 16 melanoma model, which is widely used in cancer immunology, doesn't express its own levels of Cox to that other aspirin target that gets prostaglandin that could also have been contributing to
Nick Jikomes 1:06:45
some effect. Say that again, it does not express Express Cox
Rahul Roychoudhuri 1:06:50
two. So, you know, aspirin can target Cox one and Cox two at very low levels. We think platelet Cox two because they don't have nuclei. So platelets don't have nuclei, they can't continuously replenish their supply of Cox enzyme, yeah, so they only have the Cox they were born with because they don't have a nuclei. So when aspirin hits them as an irreversible inhibitor, you essentially block the production of thromboxane by that platelet for the rest of its life. That platelets half life about seven days. So essentially that means you are achieving suppression of thromboxane a two. It was just of note that B 16 doesn't express Cox two, another potential target for us. Yeah,
Nick Jikomes 1:07:34
yeah. An interesting, yeah, just an interesting quirk of that. So, okay, so you saw this effect, this anti metastatic effect of acts of aspirin, which comes through its ability to bring down, essentially thromboxane levels. You guys were able to give thromboxane or lower it, then, on its own, modulates metastasis. What? I guess. I mean, there's a few ways we could take this, but what do you think is next here? Is this potentially very general thing of aspirin? Or do you think it's specific to Is it a quirk of certain types of cancers? Or might this be something that's a little bit more general? So
Rahul Roychoudhuri 1:08:12
in this context, I think that the value of mouse models starts so when you really start to talk about which exact tumor type into humans. I think it's best to look at the human data. So the mouse models are very good at showing general mechanisms, and it gets us to these remarkable findings, like, for example, even the discovery of checkpoint immunotherapies. PD, one, CJ four. These all arose from mouse models. But when it comes to sort of predicting which cancers might be most targetable in patients. Sometimes, I think the best source of data is such retrospective analysis is roughly done, and so from those studies, what one can see is the aspirin has a significant ability to prevent metastasis, or it may have because it's not prospective trial in breast cancer, prostate cancer and color and colorectal cancer, right? So those three cancer types are the most pronounced signals felt. But in general, there was a trend towards signal across the adenocarcinomas,
Nick Jikomes 1:09:24
I see So, so there's indications that aspirin could have an effect across at least those cancers. Yeah,
Rahul Roychoudhuri 1:09:31
yeah, and and probably broadly across adenocarcinomas. Now, additional studies, observational studies, have looked at whether this aspirin chemo preventive signal. So this ability to prevent recurrence is associated with any underlying genetics of the primary tumor, because isn't the adjuvant setting. And one set of major study that shows showed that the. Colorectal cancers with pic three ca mutations. This is a gene in COVID Three kinase alpha, which plays an important role in driving a subset of human cancers, was associated with aspirins protective efficacy. But another study also showed that HLA class one. This is the MHC molecule that presents anti T cells. That molecule, if cancers didn't express very highly that molecule, then aspirin lost its protective efficacy. So essentially, the CO rectal cancer patient that best responds to aspirin and its ability to prevent recurrence in Coronavirus cancer appeared to be dependent on high levels of MHC expression. Yeah,
Nick Jikomes 1:10:49
and would that imply that those are people whose T cells would be the maybe better able to then recognize the cancer and do something? I mean,
Rahul Roychoudhuri 1:10:58
that would imply it Yes, but these are observational studies, and I think what we really now need is high quality, prospective, randomized studies and detailed biomarker analysis to really determine the immune and non immune signals that might come into the Yeah,
Nick Jikomes 1:11:18
and so, you know, when people are thinking about, you know, scientistically, and we think about the connection between the pre clinical and the clinical world, and the mechanistic work and the translational work. You're basically saying here is, you sort of fill the gap where you looked at the literature, you found some interesting stuff. You've gone in these mouse models and shown mechanistically how this story works and the existence of this study now would be a very good justification to go in and do human clinical trials of some kind, human
Rahul Roychoudhuri 1:11:47
clinical trials and more detailed biomarker analysis. I think the study adds to a growing understanding of the prosthenoids in general, prostaglandins and thromboxanes at almost all stages in cancer development. We know inflammation drives cancer, and that some in some cancer types, prostaglandin e2, driven. We know that inflammation can potentiate suppression of anti tumor immunity in the progression phase of cancer, and that can be also related to prostaglandin me too. And here we add that actually the other prostanoids, thromboxane, a two may have this important role in suppressing T cell immunity to cancer metastasis. It's possible that prostaglandins also play a similar role in cancers that might express too.
Nick Jikomes 1:12:35
Yeah. And you know, to the extent that all of that is true, so your story is about aspirin and the metastasis of cancer. But there could be more. There could be something more general going on here, where, if you've got too much of this arachidonic acid pathway happening, it might promote metastasis and the maybe even the origination of cancer as well, to the extent it's information driven through
Rahul Roychoudhuri 1:13:01
very right so the strongest and highest quality signal so far in humans for aspirin is its ability not to prevent metastasis. That data is from retrospective studies of randomized control studies. Is pretty high quality data, but the highest quality data is in prospective randomized control studies of patients with colorectal cancer susceptibility. These patients, yeah, so these patients have Lynch syndrome. They are defects in mismatch repair. We talked about that
Nick Jikomes 1:13:33
earlier, as you mentioned, enzymes,
Rahul Roychoudhuri 1:13:37
those patients with hereditary defects so in their very germline, all tissues in their body have these defects, mismatch repair, have a very high lifetime chance of getting colorectal cancer. Now in those patients, we have randomized we have performed high quality randomized control studies of the ability of moderate doses of aspirin. 600 makes daily still not the high that the high strength, regular dosing that you would need to
Nick Jikomes 1:14:09
give it. That's a dose someone might take at home if they've got a swollen knee or whatever. Yeah, yeah,
Rahul Roychoudhuri 1:14:14
but they'd probably have to do it several times a day to achieve sort of an effect. But they take it once daily. 600 mates that can prevent cancer incidence at the rate of around 50 60% in patients with
Nick Jikomes 1:14:33
genetic predisposition. Yeah, exactly 50 to 60% yes. So that's a huge
Rahul Roychoudhuri 1:14:39
effect. This has now entered the regulatory guidance. So indeed, in the UK, our National Institute for Clinical Excellence, or Health and Care Excellence, now suggests that patients with Lynch syndrome are put on a daily aspirin. Now there is a that was the. Result of the cap two randomized control study. Now there is a randomized control study called cap three, which is now testing non inferiority of a lower dose of aspirin. Now, I think our findings also solve a bit of a conundrum, which was that most people though aspirin was given that low dose, had assumed that it was the anti inflammatory aspects that's prostaglandin two effect of aspirin that was driving these anti metastatic observations, and potentially even the primary cancer observation in Lynch. And so we're very interested in whether in humans, actually this low daily dose of aspirin is achieving its effect by thromboxane. Our mechanism would suggest thromboxane as a potential path for this, but also via T cells. So yeah, it does make a few things make sense. Yeah.
Nick Jikomes 1:15:51
I mean, that colon cancer bit that you just told us was very interesting. And again, I mentioned this the beginning. But if people are interested in this, the podcast with Halliday and yateman is very interesting. They basically have a story that came out recently, as I mentioned before, that based on basically dietary fatty acids, ultimately, but if you have, if you have a very high level of omega six fatty acids, this creates a pro inflammatory environment in the colon that facilitates colon cancer in this case. And it just feels like there's a connection there between the story that you're sort of telling on this side and some of that stuff. Because if a lot of the stuff is mediated by arachidonic acid metabolites that are pro inflammatory, all of those things sort of start to fit
Rahul Roychoudhuri 1:16:36
together. You imagine all the prosthetics throughout the cancer development journey. Yeah.
Nick Jikomes 1:16:40
Wow. So, yeah. So aspirin, obviously, you can buy aspirin over the counter. It's a very, I mean, widely, widely used drug, between the recommendations people often get to take it daily for cardiovascular related issues, between the stuff you just told us about preventing cancer in these people with specific genetic predispositions to colon cancer and the work that's coming out here. What do you think this says, if anything, about people's use of aspirin? Do you think, I mean, we don't make medical recommendations on this channel or anything like that, but what do you see? Sort of all means, you
Rahul Roychoudhuri 1:17:18
know, I wouldn't suggest anyone go out and just buy some aspirin from from the pharmacist? Because taking aspirin for long periods of time is not without risk. So we know that, especially in older people, taking aspirin carries the risk of hemorrhagic strokes. Can be lethal events. We know that chronic low dose aspirin can cause irritation of the gastric line, the stomach lining, but also stomach ulcers, and those ulcers can then bleed, sometimes in a life threatening manner, and sometimes the bleeding risk can result in loss of blood in accidents, so this loss of the clotting pathway and the effect of Cox inhibition on the stomach lining mean that taking aspirin every Day isn't without its side effects. So where aspirin is recommended is for use in Lynch syndrome or where there is cardiovascular risk, what we need is high quality, prospective, randomized control studies before we can really conclude on what is the existing controversial evidence regarding the ability of aspirin to prevent metastasis. And so One such study is now currently underway, led by Professor Ruth Langley in the use in University College London, and she has recruited to this large add aspirin trial. It's a multi center trial funded by CI UK, the UK Medical Research Council, and the Tata Memorial NIHR, which is a NHS related funder, and the Tata Memorial Foundation of India, a large multi center study to establish, for once and for all, really, the ability of daily aspirin to prevent metastasis. So they are recruiting early cancer patients. In other words, those patients with an early stage cancer that's localized within the tissue its origin, they're going to have surgery with curative intent, knowing that a proportion of those patients will have already developed undetected micro metastases. And the purpose of the after treatment, after surgery, adjuvant dosing of aspirin, is to see whether that long term, five year dosing of aspirin can prevent metastasis in those patients. So we know probably 11,000 patients in a trial.
Nick Jikomes 1:19:58
Yeah. So. Yeah, so it's a big study. I would imagine it's easy to recruit for such a study, because people are going to want to participate in that, given the hoped for effect here. So we will probably have pretty firm answers to this in the coming years.
Rahul Roychoudhuri 1:20:11
I very much hope so. And I hope that, working with the clinical trialists, we can also develop biomarkers to find out where which patients are most responsive to this so that not everyone has to go out and take aspirin. But yes, it's very promising. So one
Nick Jikomes 1:20:28
thing I want to loop back to the last thing I want to ask you about is, so the story you told us about aspirin in your study is about cancer, metastasis, broad strokes here, when people have a cancer of some kind, and I'll let you steer us in terms of you know, if there's specific cancers we should talk about. But when people have a cancer, and it sometimes metastasizes, is the metastasized cancer, like when people have cancer mortality, they end up dying from the cancer? Is it more often than not, the metastasized tumors that cause that more so than the original or not. Or what do we know there very
Rahul Roychoudhuri 1:21:06
often, it is because often those cancers metastasize to places like the lung where growth of tumors can impinge upon just create space problems you know, impinge upon a bronchus and prevent it passaging air properly, or form a focus for infection, or a cancer will grow in the bones and cause such you know, you know intense pain, or you know fractures, you know it's the growth of metastases in in places where vital functions are needed, or in the liver, you know, where so much processing of the body's diet free metabolites takes place. So, yeah, that's what kills people.
Nick Jikomes 1:21:50
Yeah. So metastasis, often is a big problem. It's not merely that there's more cancer, but it often can be what instigates the final stages, because it can go to a new organ that's even more problematic,
Rahul Roychoudhuri 1:22:03
and whereas that localized disease is amenable to curative surgery, once cancers in five different places, you know, the surge is not going to be able to cut every organ of the body and weed out every last cancer cell In the way that T cells can sometimes, well,
Nick Jikomes 1:22:22
we've covered a lot. This is, this is fascinating stuff. Obviously, it's a very relevant topic to people, just because, I mean, for obvious reasons, and it's just so, I guess fortuitous that such a common drugs, everyday drugs, involved in a story like this, that people might not otherwise think of anything that you want to reiterate, or any final thoughts you want to leave people with to do with gear. Yes,
Rahul Roychoudhuri 1:22:48
so I'd love to just go right back to why we initiated this study in the first place, and that is that you know, immunotherapies cancer, immunotherapies are really revolutionizing the way we approach cancer treatment. But a majority of those immunotherapies were developed to treat patients with widespread advanced cancer, you know, already metastatic cancer, and they've made amazing differences to some spectrum of cancers, especially those with lots of mutations. But in going earlier, in in trying to use the immune system to prevent metastasis in those patients lucky enough to be diagnosed and treated with an early stage cancer, I hope we can, we can understand that that metastases have a distinctive relationship in their early stages, when that when this single cancer cells emerge in a distant tissue and are so very vulnerable to immune attack, I think they're not only vulnerable to a weaker form of immune stimulation, so the bar is a lot lower to create an effective immunotherapy, but I think also that a distinct set of immune mediators might play an outsized role in constraining metastases, for example, NK cells, those natural killer cells that detect stressed cancer cells. Those cells are really good at weeding out metastases, and I think there's a really important therapeutic opportunity here to prevent that devastating process from happening in the first place by developing immunotherapies with dedicated anti medicine, we.
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