How exactly does metabolism power immune cells? And can we find ways to optimize this process to combat disease?
In a recent public lecture, a panel of postdoctoral fellows from Van Andel Institute’s Department of Metabolism and Nutritional Programming highlighted how metabolism and the immune system work together to keep us healthy.
Dr. Mike Dahabieh, Dr. Joe Longo and Dr. McLane Watson of Dr. Russell Jones’ laboratory are investigating how our immune cells use nutrients as fuel to carry out their function. In the future, these insights may enable cancer breakthroughs when paired with other immunotherapies.
Watch the lecture below:
Video transcript
Note: The following transcript has been edited for readability. Click a timestamp to jump to that part of the video.
Maranda [0:04]:
Good afternoon, and welcome to Van Andel Institute’s Public Lecture Series. I’m Maranda, and we are so excited that you joined us for another insightful presentation. Now, we’ve all heard the word metabolism, but not many of us know exactly what it is or how it helps keep us healthy. So, luckily, today we are joined by a panel of VAI postdoctoral fellows to guide us through and give us some exciting things to think about. Joining us today, Drs. Mike Dahabieh, Joe Longo, and McLane Watson. Together, they’ll give us an inside look at how metabolism and the immune system work together to keep us healthy and fight diseases like cancer. We’ll have a time for questions and answers after the presentation, so feel free to think about those questions during the lecture, and you can use that chat function to share your questions, and we’ll do our best to answer as many of those as we can. Let’s get things started with Dr. Joseph Longo. He will be presenting first. Dr. Joseph.
Dr. Joseph Longo [1:12]:
Thank you Maranda, and thank you everyone for joining us today. I’m going to be starting off our presentation looking at the crossroads of immunity, metabolism and cancer.
So, since we are talking about cancer today, I thought I’d give a brief introduction on what is cancer and how does it arise? And so, cancer is often considered a genetic disease, and that’s because it’s caused by mutations that occur within the cell that changes the DNA of that cell. And these mutations can be completely random. So as the cells grow and divide, it can happen by random chance or in some cases there are risk factors that can increase the chances of these mutations. So, you can think about things like tobacco smoke or UV radiation from the sun, for example. Some of these mutations don’t really do anything and the cells are fine and can function normally, but some of these mutations give that cell the ability to grow and divide uncontrollably, and that’s what leads to the formation of these tumors or collections of cells that you see in the middle there.
And as these cells continue to grow and continue to divide, they can accumulate more and more mutations, which give the tumor more aggressive properties and can even give these cells the ability to leave the primary tumor and spread to other sites of the body through a process known as metastasis. And it’s ultimately this metastasis or this cancer spreading that is lethal for, for many patients. Now, the way the tumors are shown in the figures that I have on this slide here is a bit misleading. And that’s because tumors are more than just cancer cells. There’s actually a number of different cell types within the tumor as shown in this schematic here. And obviously cancer cells make up a big part of that. But there are other cells, normal cells, non-cancerous cells that are within that tumor as well. And in particular there are immune cells within the tumor. And so, this tells us that there, our immune system plays a role in how these tumors behave and how they grow.
And so, what are these immune cells? And so, the immune cells form what is known as our immune system, and there are a number of different types of immune cells that exist. I’m not gonna go into all the different details of these different cell types today, but what I’d like you to know and what I’d like to convey here is that collectively these cells, their job is to protect our bodies from viruses, bacteria but also from cancer. And they collectively function together and cooperatively to carry out this this goal. And I just wanna highlight one subset of these cells, in particular known as T cells, which is the main focus of research in the lab, in our lab, in the Jones Lab at Van Andel Institute. And it’s gonna be the main cell type that we talk about today during our presentation.
So, what are T cells? T cells are the body’s soldiers of host defense, and they come in two main flavors. The first being CD4-positive T cells. And you can think about these cells as the generals of the army. Their goal and their job is to direct other cells during an immune response and lead them to do what they need to do. You also have CD8-positive T cells, and you can consider these as the ground troops. These CD8-positive T cells, their job is to to identify and kill infected cells or cancer cells in our body. And so, on the right I show an image there, where the cancer cells in magenta and they are being targeted and recognized by CD8-positive T cells in that blue cyan color. And you can see that these CD8-positive T cells are interacting with those cancer cells and actually triggering them to die.
So, how does this actually happen? How do T cells in our body recognize and kill cancer cells? So as cancer cells within the tumor die off, they release pieces of themselves into the circulation in our body. And so, if you remember from the very first slide I showed, cancer is a genetic disease, and it’s caused by mutations. And so, some of these pieces that are released will be, will resemble what’s found in normal cells in our body, but some of these pieces will be different. They’ll be mutated because of these genetic mutations. And it’s these mutated pieces of the cancer cells that are more likely to activate our immune system. These tumor pieces can be taken up by specialized immune cells in our body, known as antigen-presenting cells, or APCs, and they take these pieces of the cancer cell and decorate their surface with them, and then they circulate around the body and when they come into contact with their partner T cell, they present that piece of the tumor of the cancer cell to the T cell, which will trigger them to become activated.
These activated T cells will then grow and rapidly divide and make multiple copies of themselves, essentially creating this army of T cells, which will then travel back to the tumor. And once in the tumor, these T cells will interact with those cancer cells and release factors that will trigger those cancer cells to die. And then as those cancer cells die, they’ll release more pieces of themselves, and this cycle continues over and over again. But the way it’s shown here is sort of a best case scenario or kind of what happens in a, in a perfect world. It doesn’t always work this perfectly. And that’s because within the tumor, T cells often become dysfunctional and they actually lose their ability to attack and kill cancer cells. Which brings us to sort of the main research question we have in the, or the main goal we have in the Jones Lab at Van Andel Institute, and that is to identify new ways that we can improve T cell function within the tumor.
And the way we do this is we take a metabolic approach to this research. And the reason for this is because T cells need a lot of energy and nutrients to carry out their activation, their growth, and their proliferation and function. So just like you and I need to consume calories and burn calories to get energy to do our day-to-day functions, the cells within our body also need nutrients. They also need metabolites, and they need to burn them as fuels so they can get energy and other materials that they need to do their jobs. And so, for a T cell to become activated and to attack cancer cells, that function is highly dependent on the availability of nutrients in their environment. And importantly within tumors and in the context of cancer, metabolic defects are central to how these T cells become dysfunctional. So, in other words, if T cells within the tumor don’t have enough access to the nutrients they need to function properly, this causes them to lose their ability to properly control tumor growth. And, so, a major focus then of our research is to identify which nutrients fuel T cell function, and how can we leverage this knowledge to create immunometabolic therapies to improve our immune system’s ability to to identify and kill cancer cells.
Okay, so, then that brings us to what are these nutrients that T cells need to function, and where do they come from? And, so, what nutrients fuel T cell function is actually an active area of research in our lab. Recently, we’ve identified a number of different classes of nutrients that are important for T cell function. And Dr. Watson will talk a little bit about this in his section of the talk bit later on. But where do these nutrients come from? They can actually come from a number of different sites or a number of different factors can contribute to nutrient availability in the body. A big one is the diet, right? What we put into our bodies will dictate what’s available for the for our immune system and our immune cells to use and carry out their function.
So, diet is a big, a big player. There’s also whole-body metabolism, right? The different organs in our body will consume and break down and release different nutrients into our blood. And this provides a source of nutrients and metabolites for our immune system to potentially tap into and use to carry out their function. And then you have the microbiome, right? These are the bacteria that live in us and on us, and they are also metabolically active and will release different metabolites that we may not necessarily get from diet or from the organs and natural cells of our body. And some of these microbe-derived metabolites can also contribute to how T cells behave and, and function. And so, there’s a number of different factors that can play a role here and that we need to consider. And so, for the remainder of my time, I really just wanna highlight one class of these nutrients known as ketone bodies, which our lab recently found as being an important class of nutrients that fuel T cell function not only in cancer, but also in the context of infection as well.
And so, ketone bodies are nutrients that are produced by, primarily by the liver. And they’re produced when glucose levels in our blood are low. And so, we can achieve this typically, for example, through fasting. So, if we reduce how much food we intake, that reduces glucose in our blood, and that will trigger our liver to make ketone bodies as an alternate fuel source for ourselves. And many of you may have also heard of a ketogenic diet. So, these are low-carb, high-fat diets that will also induce the production of ketone bodies in our bodies through the liver. But what we have found is that ketone bodies can actually drive T cell function, and they’re actually quite an important nutrient for optimal tumor control in in the body. And so just to depict that, I’ll show one piece of data here.
This is looking at tumor growth. These are colorectal cancer tumors grown in mice. And what this graph is showing is the tumor, the size of the tumor over time. And so that bottom solid gray line is the growth of these tumors in mice that have functional, normal T cells. And so, you can see over time you get a gradual increase in in tumor growth. But this top line here are those same cancer cells, but these are injected into mice where we’ve genetically modified the T cells so that they can’t metabolize ketone bodies. The ketone bodies are still there, they’re still present. It’s just that the T cells in that mouse are not able to use it as a fuel. And what you can see is that those tumors in those animals grow much quicker and much larger when those T cells can’t use ketone bodies as a fuel source.
And what this tells us is that the ability to use ketone bodies and to be able— the ability to metabolize ketone bodies is important for optimal tumor control. And so, with that information, if we prevent T cells from using ketone bodies, it makes them less functional. Can we use that information to, say, increase ketone bodies, and does that in fact make T cells more functional? And so, this is an active area of research now in our lab where we’re trying approaches that will increase the availability of ketone bodies in vivo. And as I mentioned before, we can do this through a number of different dietary means. I mentioned a ketogenic diet before, but calorie restriction is another way that we can achieve this just cutting the amount of food we intake on a daily basis. Fasting is another way to do this.
So, lowering or abstaining from food for a certain period of time, or intermittent fasting, these are all dietary strategies that lead to an elevation of ketone bodies in our body. And so, what we’re trying to do in the lab now is we’re asking questions. Can we combine these specialized types of diets with immunotherapies to improve T cell function in tumors and improve the response, the immune response to two different types of tumors. And so, like I said, this is an active area of research currently in the lab. We’re making some interesting findings here, and hopefully in the next little while we’ll be able to share some of those results with you. But this is again, something we’re very excited about leveraging diet and combining that with immunotherapy to potentially treat cancer. So, with that, I’ll pass it on to Dr. McLane Watson, who will tell you a little bit more about nutrient availability and T cell function.
Dr. McLane Watson [13:39]:
Alright, thanks Dr. Longo. So, sticking with this idea of metabolism and T cells as Dr. Longo mentions, metabolism is kind of the set of life-sustaining chemical reactions in an organism. And when we normally think — at least most of us probably think — of metabolism when we hear that word as this full system whole body metabolism, you might talk to your neighbors or friends and they say, “Oh, I have a really fast metabolism,” or, “I have a really slow metabolism.” That seems, that’s kind of on a global level. However, metabolism actually can be broken down into different levels. So you could think of whole body or system metabolism, right? But you can also think of metabolism on the level of organs. So your heart, your lungs, your eyes, those all are going to function slightly differently, metabolize things slightly differently, to sustain their particular function. And of course, you can go even further down to the single cell level like immune cells or even individual muscle cells, and those cells are gonna take up fuels and use them again to support their particular function. And, as Joe has already mentioned, the R. Jones lab of which we are a part of has this special interest in T cell metabolism.
So, T cell function is highly dependent on nutrient availability. T cells circulate in the blood, and so because of that, they can find themselves in almost every tissue and organ. So, they’re in the blood, they can become resident in different tissues. So, they encounter things, you know, like tumor fat tissue or adipose tissue, intestines, and each of these, as I said has their own kind of metabolic microenvironment where nutrient levels are going to be different depending on the tissue type that you’re in. So, things like tumors, they have low oxygen and high lactic acid, adipose tissue has high fatty acids, whereas the intestines might have things like high acetate, high butyrate. So, the metabolic landscape of each of these tissues varies. However, T cells need to be able to function in each of these diverse environments. And luckily for us, they have adapted and are metabolically flexible to be able to maintain that pathogen and cancer-killing function in all these different environments.
However, that being said, not all fuels are created equal. So, things that may be available in one tissue, while the T cell could use it, it doesn’t mean that it’s gonna be using it at the optimal state, or that’s the optimal fuel to fuel the best function of that T cell. So, for this idea, I kind of like to think of T cells as cars. And this is a, a graphic done by Matt Vos in our lab depicting two different potential fuels for T cells, so glucose and ketone bodies. But I like to think of T cells as cars because of course, different cars can function on different fuels. So, you’ve got diesel, gasoline, E85, electric. And as most of us probably know, if you put regular gasoline into a diesel or vice versa, that’s gonna completely destroy the engine.
But then you have some cars that are actually flexible in their fuel choice, like that can take E85 or gasoline. But if you’ve ever used one of those cars, you know that depending on the fuel choice there, that actually impacts performance. E85 might give you a boost in pep, but you get lower gas mileage. So, there’s trade-offs, and what fuel choice you choose matters for what performance and output you have. So, looking at that idea, fuel choice really matters for optimal function, and it’s the same with T cells. So, how do we actually find what the best fuel for T cells is? So, in our lab we turn to serum as this list or menu of potential fuels that T cells could utilize.
So, serum is a part of the blood, and you can see actually, if you take blood out — you see the vial on the left — if you let it coagulate, all the red blood cells will clot at the bottom, and then you’re kind of left with this yellowish liquid, and that contains a lot of nutrients like fats and sugars and anything that your body makes from all these different organs. And because they’re all filtered and innervated with the blood it’s kind of a good average of what T cells might encounter in, of course, the circulation, but in individual tissues as well.
And so, what we did is looking at that menu, we saw, okay, what are metabolites that are at a pretty high concentration, and can we then put on T cells and test how that impacts their function? And so, we did that. We identified about five metabolites that had appreciable concentrations in the serum, and we tested their impact on T cell function. And to make a long story short, what we found, really, were these three particular metabolites — acetate, lactate, and as Joe mentioned, ketone bodies — were really important for improving T cell function.
So, when we had those metabolites present with T cells, and T cells had the availability to use them, we saw improved cytokine production, which, cytokine production is important because of those excreted molecules that kill tumor cells and help clear virus. And then we also improved their ability to proliferate or make more versions of themselves. So, this is really interesting to us that just by giving them the right fuel, again, they still function without these fuels present. However, with the fuels present, they function even better. So, this is kind of, it’s this idea of there is this optimal fuel choice. It’s like, yes, you can get away with not having it, but you’re better off if you do have it.
Um, okay, so, we now know some fuels that help T cells work better. But a big question remains is how does the engine work? Essentially how do those T cells use that fuel to give that functional output? And of course, knowing how this engine works is key to identifying the best fuel. With cars, of course, we design cars’ engines to use a particular fuel, but in this instance, we kind of have to reverse engineer what we know about the engine from what we’ve identified fuels to be.
So, the, that kind of brings me to this idea of epigenetics as a link between fuel and function and maybe this idea of epigenetics can be that engine and how T cells actually utilize these fuels. So let me explain what epigenetics is. So, we’re all probably familiar with the idea of DNA, and DNA is this blueprint that encodes essentially how to build a cell. So, if you look all the way on the right, you can see this nice double helix strand of DNA. And every cell in our body contains the full blueprint to build every other cell, yet we have distinct cell types. So, our eye cell, our liver cell, our lung cell has all the same information contained within it, but clearly those are very different cells. So, to fit the DNA into each cell, it must be neatly packaged.
And so, that’s what’s depicted in this middle and far left picture, is that we see that the single strand of DNA are wrapped around these proteins called histones, and then those histones can kind of be wrapped around each other to make these chromatin fibers. And so, you get this kind of hierarchy of packaging. And what you can appreciate is that because the DNA is wrapped around these histones, depending on how tightly wrapped or how loosely wrapped it is can really control access to that part of the blueprint. So, you can imagine if it’s tightly wrapped, that closes off that part of the blueprint, but if it’s open, then that part of the blueprint is available to read. And so, that’s the idea of epigenetics. Epigenetics is really the control of this gene expression by altering the accessibility to DNA or accessibility to read those genes and then produce functional proteins.
So, how does that, again, play into this engine idea? Well, metabolites are actually used to be able to control that DNA accessibility and DNA accessibility controls function. So, here you can see on the left, the closed or like tightly packed DNA, leads to inert or non-functional T cell. Whereas on the right you can see those the DNA is accessible and that can lead to a functional T cell. And this control of open and closed are dictated by these metabolites: acetyl-CoA for the open, or S-Adenosylmethionine, or SAM, for the closed. And so, depending on how these histones are modified by these metabolites, which come from the fuels that we described, like acetate and glucose, lactate, ketone bodies, that can control whether things are opening and closed. And that opening and closing can control ultimately how T cells function. So, this may be how T cells are using those fuels to increase their performance and output.
So, to kind of summarize, we really need to understand T cell engines and fuels because that’s gonna be key to improving diseases, especially diseases like cancer. So, what we know from the past 20 years of kind of cancer immunotherapy research is that almost every cancer immunotherapy treatment relies on optimal functioning of T cells. So, it’s vital we understand how we can make T cells function better. Also, to optimize performance of T cells, we have to understand how their engines work, what sorts of we identified some fuels, but what if those aren’t actually even the best fuels that T cells could be used? So, really, if we can understand the inner workings of the T cell, we can really fine tune and produce strategies to develop new interventions to improve cancer immunotherapies. So, I hope this idea of kind of fuel engines and T cell sticks with you today. So, I’m gonna pass off the talk now to Dr. Mike Dahabieh.
Dr. Mike Dahabieh [25:52]:
Thanks a lot Mac, and thanks Joe as well for providing intro to that. So, as Joe kind of mentioned earlier, T cells, they can become dysfunctional or enter this exhausted state. So, this happens upon constant exposure to cancer cell-specific protein fragments or antigens. And this is actually what causes T cells, or this is one causative factor, where T cells become exhausted or dysfunctional. And we can kind of see that in a cartoon here where they really exhibit markers of fatigue. And so, features of exhausted cells include decreased cytokine production. So, cytokines are these molecules or proteins that T cells release that actually go and kill target cells. So, in this case, cancer cells. And when T cells see a foreign protein fragment, whether it’s from a virus or from, abnormally, from a cancer cell, they are triggered to proliferate so that they could tackle that problem.
And so, another feature of exhausted T cells is a low proliferative capacity. And so, I’m gonna talk about this throughout my portion of the talk, but there’s a protein called PD-1, and this is elevated and this is on the surface of T cells and this is one hallmark of exhaustion. And so, I’ll get into a little more of those details here. So, shown here is PD-1 on the T cell and, for example, PD-L1, which it binds to on a tumor cell. And so, when those two engage with each other, and that’s a protein-protein interaction, that actually shuts down the T cell so that the tumor cell now can proliferate. And so, some of us might be familiar with immune checkpoint inhibitors. And so, PD-1 is an immune checkpoint. And so, when you inhibit PD-1 from interacting with PD-L1, what happens is now the T cell is no longer exhausted, and it can secrete cytokines which ultimately kill the tumor cell. And so, this is really revolutionized how we combat cancer in the clinic. And immune checkpoint inhibitors, or ICI, durability — this is limited, however. It works really good in some cases with up to a hundred percent response, but in other cases you can have no response. So, on average you have about 50% of cancer patients relapsing or not even responding. So, this has really revolutionized how we treat cancer in the clinic, but still preventing T cell exhaustion remains a significant therapeutic challenge.
And so, there’s different types of immune checkpoints that exist. So, just to give you a little refresher here, on T cell on the bottom, you have them expressing high levels of this PD-1 protein, and in a non-T cell. So, a good example is a cancer cell, those express PD-L1. And so, you have this protein-protein interaction that occurs that actually shuts down the T cell and enforces that exhaustive state. Now this was discovered about 10 years ago. And you can also have nucleoside-protein interactions. So, nucleosides are these are kind of the building blocks of DNA, and in this case, you have adenosine which is sourced not from a T cell, interacting with an adenosine receptor, in this case A2AR on a T cell. And so, another type of interaction that occurred that enforces exhaustion is when you have something called, on the bottom right here, PTGIR.
This is a prostacyclin receptor on a T cell interacting with a lipid. And this is derived from a pathway that I’ll get into, but this is a metabolite that is circulating in tumors and throughout the body. And when prostacyclin, the lipid, binds to the protein PTGIR, this enforces a state of T cell exhaustion. And so, what I want to note here is prostacyclin is derived from arachidonic acid, and this can be found in fatty fish and meat and also too, which is really cool. And this is thanks to funding from, from donors, such as those tuning in right now, this was discovered in T cells at the Van Andel Institute. So, there’s different types of therapies that exist and I just want to take a little pit stop here to talk about these. And then we’re gonna get into what happens when we modulate the prostacyclin receptor or PTGIR in T cells.
So, I kind of went over this earlier. There’s immune checkpoint blockades or immune checkpoint inhibitors. So, a prime example is anti-PD-1, and when you intercept that interaction of PD-1 and PD-L1, this revitalizes exhausted T cells. So, you can also have chemical therapies or radiation. Here I’m just showing a chemical that works to combat a B-cell lymphoma called ibrutinib, and we often use chemicals to combat cancer too. And also, one thing that’s starting to gain traction in the clinic, and we use this heavily in mouse models actually, is T cell therapy. And the basis behind this is that from a host — so, in this diagram here, a human, you take T cells out, you can genetically engineer them to perform better, and then you re-infuse them back into, in this case a cancer patient, so that those T cells can now better combat cancer.
And so, as I mentioned, we modeled this a lot with mouse models of tumors. And just touching base here, coming back to PTGIR, here’s an experiment here where we looked at melanoma growth in a mouse model here. So, as Joe kind of touched on this earlier, you have tumor volume on the y-axis and days post-tumor injection on the x-axis here. Now in this melanoma model here, on day zero, we injected melanoma into these mice. And then, on day seven, we transfer in two different types of T cells into two different cohorts. So, in the red, these are T cells with very high PTGIR expression that we put in. And as I mentioned earlier, when you have high expression of PTGIR, this is a driver of T cell dysfunction. And so, when we look at tumor growth over time compared to, in black, normal T cells that were transferred in, see that in red, the tumor volume is quite high, meaning T cells transferred in with high levels of PTGIR poorly controlled tumor growth in a melanoma model.
Now we can look at this in the opposite case where what happens — and this has more therapeutic relevance — what happens now if we transfer in normal T cells and PTGIR-ablated or PTGIR-deleted T cells? And you can see here, in green, when we delete PTGIR from T cells that we transfer in, we see low tumor volume. So, really good control of that tumor growth. And just to expand this to other models, too, we’ve tested this in virus models. But just to keep on the topic of cancer, in a colorectal cancer model, we see a very similar pattern to the last slide where if we transfer in normal T cells with standard PTGIR levels, those tumors grow pretty high. And that’s shown with the black circles. But if we delete PTGIR from these T cells that we transfer into a tumor-bearing mouse, you see pretty good control and you see a low tumor volume and that’s shown with the green circles there.
And so, just to kind of touch back here, I really highlighted a novel lipid protein immune checkpoint, meaning on T cells, that protein is PTGIR and then is expressed very high when those T cells are dysfunctional. But it’s binding a lipid in this case, not another protein, it’s binding a lipid, prostacyclin. And so, this really leads to some further questions into, in tumors, what is the source of prostacyclin, where is it coming from? And also, to, really, thanks to money that we get for this research, this has really led to a provisional patent where we’re aiming to delete PTGIR in T cells and use this as a therapy ultimately for humans. And we have some experiments on the horizon, too, where we’re gonna test molecules and potentially blocking antibodies down the line, kind of like anti-PD-1, where we could block this PTGIR-prostacyclin interaction in mouse tumor models first and then hopefully take that to the clinic with humans.
And so, just to kind of wrap up everything here, too, some take-home messages from all of this — and this is the last slide here that I’ll show — is that as Joe touched on, really, you are what you eat. Diet impacts immune cell function, but also the microbiota, which live in our gut, can also influence immune system and immune cell function, too. As Mac touched on here fuel choice matters for optimal T cell performance, and you can have different fuel choices present in different tissues. But also, you can have different fuel choices present during the course of, for example, tumor progression. And so, really defining what fuel cell or what fuels will boost T cell performance at a given time is really a key part of this research. And just to wrap up here, as I showed this prostacyclin-PTGIR interaction is very important, and metabolites can control T cell function from outside the cell too. So, prostacyclin is not internalized by a T cell necessarily, but binds to this receptor and really shuts down those T cells and causes them to be exhausted. So, thank you very much for your time. I’m gonna hand it over to Maranda now.
Maranda [35:42]:
Thank you so much to each of you. We appreciate your insights. I have a lot of questions and I’m sure many of you do as well who are joining us. Don’t forget, use that chat function. Go ahead, send those messages in or those questions, and we will try to get to as many of them as possible.
I’d like to get started based on some of the things I heard you discuss. Dr. Longo, we’ll start with you. You mentioned that the immune system is affected by diet, and I think we all are wondering what can we eat to, to build up our immune system, and that, if we do have cancer currently, are there things that we can eat to help us as we work through this journey with the disease?
Dr. Joseph Longo [36:24]:
Yeah, that, that’s a great question. So, I would like to start off by just saying that a lot of what I’ve shown is done in mouse models. So, you know, how effective this is in patients is still yet to be determined. And I think this whole concept of diet as an anti-cancer therapy has gained a lot of, a lot of traction. You can find a lot of resources that, you know, will talk about the anti-cancer diet and what’s best for, for certain types of cancers, but I’d like to stress that a lot of that hasn’t been, at least not yet, backed up by rigorous scientific investigation. And that’s what, mainly, what we’re trying to do in the lab now, is take these different diets — ketogenic diet, calorie restriction, intermittent fasting — which you’ll hear a lot about in popular culture these days, but really take that to the bench and really say, “What do these diets do to cancer, to our immune system, at a molecular level?”, to really understand the mechanism of how these work.
So, what I will say is we don’t have, you know, the one-diet-fits-all. You know, “If you have cancer, you should go on this diet.” I mean, your typical healthy eating behaviors that are typically recommended by your doctor are your, sort of, your best go-tos.
But we’re really looking now at not necessarily switching diets, but can we take these different diets and combine them with certain therapies under specific conditions to make those therapies more effective. So, there really isn’t a sort of a one-answer-fits-all to that question. It’s very much work-in-progress, and we are hoping in the future that our, the research that we do in the lab can be translated to clinical trials, for example, to really test these diets in a controlled environment in patients to get answers to those very questions. So stay tuned. Hopefully we’ll have some answers to that in the near future.
Maranda [38:08]:
Keep working on it, because we do want that one-diet-fits-all <laugh>. We will go to Dr. Watson. You had talked about the analogy of the car. I really like that, that makes it very clear for us to understand. But when it comes to the work you’re doing in your lab and fighting cancer, what’s better: a faster or a slower metabolism? Is one better than the other?
Dr. McLane Watson [38:32]:
That is a, that’s a good question. The, I guess I, when I hear faster and slower metabolism, I always think, again, back to that level of are we talking about a whole-body system metabolism? Are we talking about T cells? Are we talking about specific organs? So it’s hard to say necessarily faster or slower in this context. I will say when it comes to T cells specifically, usually if they can, there’s these two ideas of kind of main metabolism modes where you have a glycolytic mode and an oxidative mode. Glycolytic is a fancy word; it uses glucose and sugar to break down and metabolize, versus an oxidative, you’re more using oxygen as that fuel source. And when T cells are able to use oxygen they are actually better at killing cancer cells. So, in that context, if we can kind of boost the oxidative or the oxygen side of things that seems to be really good at killing cancer cells. And that could be supported through many different ways as we’re trying to explore, like, maybe diet does that, maybe there’s some inhibitor or drug that we can treat that will do that. So, again, yeah, still trying to work all those things out.
Maranda [40:13]:
Dr. Dahabieh, you had talked about exhausted T cells. I don’t want exhausted T cells. We want our T cells to not be exhausted. What causes that? And is there anything we can do to prevent it?
Dr. Mike Dahabieh [40:30]:
Yeah, that’s, I think, the million dollar question. So, I think we have some insights into what the causes are. So, I kind of touched on, you have constant presentation of these foreign protein fragments from, for example, a cancer cell to a T cell. That’s one of the causes. And I think what our research in the lab has shown is that you’re not restricted to these types of interactions. You can also have a lipid like prostacyclin interacting with the receptor, and that also drives T cell exhaustion.
So, in terms of how we can combat that, I think this is a very, very active area of research. And I think we’ve only touched the tip of the iceberg in terms of therapies like immunotherapies, like anti-PD-1, anti-PD-L1. And so, it’s ideal to have cells that are not exhausted, so that they can perform well. However, this is often an issue in the clinic, in that we need to balance that switch in terms of not hyperactivating these T cells, because when you have T cells that are hyperactive, you can end up with an immune response that actually is not good to the host. So, this really— finding new things that are driving exhaustion and finding better ways to revitalize these T cells is a very active area of research right now.
Maranda [42:01]:
Thank you. Next question, this is for Dr. Longo, would you kindly clarify whether the mutated pieces released from dying tumors, which activate the immune system, are considered tumor-specific antigens or tumor-associated antigens?
Dr. Joseph Longo [42:19]:
Yeah, so that, that is exactly right. So those, the antigen is … the piece that is being presented to the T cell from those antigen-presenting cells. And so, those are what are more likely to indu— or to activate your immune system, because typically, your T cells, they’re your body— in a perfect world, your body trains your T cells so that they don’t react to normal pieces of your cells because you don’t want your T cells attacking your own tissues, your own organs, your own, your own healthy cells. But in the case of cancer, cancer actually is part of our, it was a normal cell that became transformed, that transformed into cancer. And so, its origin is actually our own cell. It’s not like a foreign virus, a foreign bacteria. And so, a lot of the stuff that cancer cells have are shared with many different cells in our body.
And so, we don’t want our immune systems reacting to those normal, like, pieces. But because of mutations occur in certain cancers and some cancers have higher mutational burden than others, it creates what we call tumor-associated antigens. And it’s these tumor-associated antigens that are more likely to result in activation of T cells. And then those T cells recognize, they are able to understand that that is not quite right, it’s not quite normal, it shouldn’t really be there. And so, then they’re trained to go back to the tumor and kill cancer cells that have these tumor associated antis associated with them. So that, that’s exactly right. Yep.
Maranda [43:57]:
I will let you all decide on this one. Do you know of any, anyone who is developing a gut-building script or a plan for patients to follow post colonoscopy? Wouldn’t that be the perfect time to remodel the gut?
Dr. McLane Watson [44:15]:
I think I have a good answer to this one. So, there’s some really cool research being done, not necessarily in our lab, but in the field of cancer immunotherapy, where people are taking a real interest in the gut microbiome and how that influences response to, like Dr. Dahabieh said, the anti-PD-1 therapies and like the immune checkpoint blockade.
And so, what they’re actually doing is they’re taking patients that respond to that immune checkpoint blockade, so the tumors grow, or the tumor growth stops or grows slower. And then they’re actually taking like fecal-matter transplants out of those patients, transferring that into patients that don’t respond to PD-1, and then seeing that that actually produces a response now in those non-responders. So, essentially you can use poop to, you know, get people to respond to PD-1 therapy. So just, that— we don’t necessarily understand exactly how all that is happening. Of course, that has to do with the microbiome. People are very interested in what particular microbes are conferring that effect, or if it is a particular microbe or what about that works. But definitely can use that to remodel the gut from a kind of microbiome standpoint. So, it’s possible. People are working on it.
Maranda [45:51]:
Interesting. Next, one of our viewers says that they have always heard that a keto diet, while beneficial to avoid cancer, can be dangerous for those with diabetes or pre-diabetes. Any thoughts on that? And are you recommending the keto diet then to avoid cancer?
Dr. Joseph Longo [46:09]:
That’s a good question. Yeah. So, keto diet does definitely have pros and cons. It’s— there is the aspect of, there’s this thing called ketoacidosis where you can have too high levels of ketone bodies in your body, and you want to avoid that. And definitely there is the risk factor with diabetes there. So, it’s not, you know, something that every person with cancer should be going on. We’re definitely not advocating for that. But what we’re trying to understand is how we can safely increase the amount of ketone bodies available to the T cells. So, a keto diet is one potential strategy that we can do this. We’re also looking at ways of, you know, maybe a ketone supplement or, you know, figuring out what the ketone bodies are doing to the T cell so that we can manipulate it, bypass the ketones entirely, and manipulate that pathway in the T cell.
So, there’s different approaches that we can take, but definitely there— and with any kind of diet it’s not gonna be, you know, for everyone. And there’s definitely, especially in cancer patients, because when, you know, you’re afflicted with cancer and you’re going through treatment, a lot of times, diets, a lot of times nutrition is not as, you know, you know, you and I might have, you know, our, our, our daily, you know, calorie intake for example, a lot of people don’t feel hungry or don’t eat as well. And so, there’s special dietitians that work with cancer patients to try to keep up their nutrition as they go through certain therapies and things like that.
So, trying to figure out how to incorporate some of these diets and how you know, we’re trying to look at it from the perspective of T cells, but also and boosting T cell function, but how does it affect the cancer cells? How does it affect other cells in the body? We kind of need to take a step back and look at the entire patient, you know, what do these diets do systemically that may benefit, or not, a particular cancer patient. And there’s a lot of research being done out there showing that ketogenic diet can starve cancer cells of certain nutrients that they need to grow as well. And so, but, through our research as well, there are some cancers that can use ketone bodies as a fuel similar to T cells. So, figuring out which cancers might benefit, which won’t and what that does to the entire patient, I think, is we need a lot more work in that, in that area before we can recommend how these diets are gonna be used going forward.
Maranda [48:29]:
Well, thank you for continuing the work. We appreciate it. Next question, how is your research affected by changes in food production, like processed foods or plant-based meats? Have any of you had any connection with that?
Dr. Mike Dahabieh [48:45]:
I could touch on that. So, we haven’t really actively been studying that, but I think there are some labs that investigate that. And it would be interesting to see how T cells perform, for example if you compare mice on a diet with, for example, organic versus non-organic, and we don’t know the answer to that question at the moment. I know this is kind of a big thing that’s gaining traction in terms of what we’re putting into our body, how this can influence the performance of cells. So, in terms of our research, we don’t necessarily study that, but I think with a lot of advanced, for example, there’s a lot more advanced farming techniques out there and the purpose of this is to have crops of higher quality. So, how this impacts our immune system, I don’t think we know the complete answer to that. I think we’ve kind of touched on the surface and understanding how specific things in these foods impact immune cells should be studied, I think.
Dr. McLane Watson [49:54]:
Yeah, and I’ll just jump in and add one thing that, here at the Van Andel Institute in the metabolism department, there is a lab that’s very interested in looking at different types of lipids or fats and looking at, depending on how— where those fats come from. So, if you have animal-based fats or plant-based fats, how that one impacts how tumor cells function. And then also they’re looking at the cross, like, of that and how immune cells respond to those different types. So, there’s definitely work being done and it’s a very active area of investigation.
Maranda [50:37]:
Are there any changes that we can make in our daily lives that can contribute to a healthier metabolism? What’s your personal opinions?
Dr. Joseph Longo [50:48]:
Exercise?
Dr. McLane Watson [50:49]:
Yeah.
Dr. Mike Dahabieh [50:53]:
I think stress, you know, I think when we’re stressed out, you tend to get sick a little bit more. So, I think managing stress levels in a healthy way, whether it be exercise or other things that are good for your body impact your immune system.
Dr. McLane Watson [51:11]:
Yeah, it seems like kind of a cliché answer, but I mean, kind of the things that we know of exercise, good diet, getting good sleep, all of those can factor into improving immune systems. And, of course, like, each person is very different and they’re gonna have different beneficial effects from sleeping more or eating certain things. So, it’s hard to say and it’s kind of vague answer, but I think it’s just like, you know, the, probably the things you know that are healthy for you, that’s what you should be doing. <Laugh>
Maranda [51:50]:
Alright, as we wrap things up, I would like each of you to answer this question. The work you’re doing is wonderful. It is also probably slow-going, and we would like to know what excites you right now about the work you’re doing and brings hope to us moving closer to discovering things that could benefit all of us. Dr. Watson, you go first.
Dr. McLane Watson [52:18]:
Oh, alright. Yeah, for me, I am really excited about, again, finding out how those T cell engines work. I’m always this very detail-oriented person and from an outside perspective that might seem like why are we trying to get down into the minutiae of all these things? How is that really gonna impact cancer therapy? But some of the best and major discoveries that have really moved cancer treatment forward have been from these sort of basic research, understanding how T cells work, and then once we figure out how to, how it works, how we can manipulate it, and that has, you know, caused the immune checkpoint blockade, the adoptive cell transfers, our T cells, all sorts of things that are just revolutionizing cancer. So, I’m really excited that this is a area that can be really, really fruitful if we invest our time here.
Maranda [53:18]:
Great. Dr. Longo?
Dr. Joseph Longo [53:21]:
Yeah, so, I’m really excited about the potential of combining diet with existing cancer therapies to try to improve them. I mean, there’s a lot that we still don’t know about how these diets work, but I think we’re at the point now where a lot of people are interested in understanding exactly, you know, how they work and how they can be used. And, you know, these diets, they exist, they’re pretty easy to manipulate. You know, you don’t have to develop a new drug to make things more effective, right? The diets are around, they’re available, the food is there. So, if we know how we can use it smartly, together with immunotherapy, chemotherapy, other types of therapies that are used to treat cancer. And if we can use it in a way to improve patient outcomes, and I think that’s an immediately actionable area where we can invest time and resources to have a timely impact, I would say, on cancer patient care.
Dr. McLane Watson [54:13]:
Dr. Dahabieh?
Dr. Mike Dahabieh [54:14]:
I think what excites me is that, you know, all the literature really is surrounded against PD-1 and PD-L1 and the immunotherapies that are in the clinic are still very restricted to intercepting these protein-protein interactions. And what really excites me is that we discovered here at the Van Andel that we have a protein-lipid interaction that is really driving T cell exhaustion. And it is slow-going, of course, this type of work, but I think what really fuels me right now is the patent and also testing drugs that are currently out there that actually inhibit the prostacyclin receptor. But they’re used for a totally different purpose. I mean, we discovered we were the first to discover this receptor exists in T cells. And so, to repurpose a drug that’s used to actually control blood pressure, so for a totally different purpose, if we could repurpose that for cancer therapy, I think that would be a grand slam. So, I always think about that and that always motivates me and excites me.
Maranda [55:24]:
Well, we are cheering you all on for a grand slam. Thank you so much. Thanks again. We’re giving you a round of applause. We appreciate your time doing this. I also wanna thank everyone who joined us in our audience today for this discussion. If being a part of this was exciting for you and you’re saying, “I wanna learn more about the good work being done every day,” we would encourage you to go to our website, vai.org, and you can learn all about all of the different efforts. You can sign up for our newsletters that we have. We have a lot of events that inspire engaging conversation. This is our final Public Lecture Series for 2024, but please mark your calendars on Feb. 5. We will have Dr. Melissa Hoyer, she will be leading us in a discussion on neurodegenerative diseases. And you can also stay tuned on our website to learn more about that. So again, thank you so much to our presenters as well as each of you in our audience today for joining us, and I hope you have a great day where you live. Thank you.