Bacteria May Hold The Key To Cancer Immunotherapy
Cancer immunotherapy, especially a type known as checkpoint inhibitors, has given new hope to many people with cancer. The treatment takes the brakes off the body’s own immune system, allowing it to attack tumor cells. But some people respond to the therapy, while others don’t—and it’s not entirely clear why.
In recent years, researchers have been looking into the microbiome—the collection of microorganisms that live in and on your body—for clues. Studies have found that there’s a microbial difference between people who respond to immunotherapy, and those who don’t. Research recently published in the academic journal Science, suggests scientists may have finally unraveled how one of those bacteria has an effect.
The researchers discovered that Bifidobacterium pseudolongum, a species of bacteria found in elevated levels in the tumors of mice who responded well to immunotherapy, produces a small molecule called inosine—and that under the right conditions, inosine can help to turn on the immune T cells needed to attack a cancerous tumor.
Kathy McCoy, one of the authors of the study, and the director of the IMC Germ-Free Program at the University of Calgary, joins Ira to talk about the study, and the challenges of raising mice without any microbiome at all.
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Kathy McCoy is a professor in the Department of Physiology & Pharmacology and the director of the IMC Germ-free Program at the Cumming School of Medicine, University of Calgary in Calgary, Alberta, Canada.
IRA FLATOW: This is Science Friday. I’m Ira Flatow. Cancer immunotherapy spurring the body’s immune system to fight cancer has given new hope to many people with cancer. It takes the brakes off the body’s own immune system, allowing it to attack tumor cells.
But there’s a flaw. In some people, the therapy works very well. In others, not at all. And it’s not entirely clear why or what the differences are between people who respond to the therapy and those who don’t. In recent years, researchers have been looking into the microbiome, the collection of trillions of microbes that live in and on our bodies, looking to the microbiome for clues.
Is there a bacterial difference between people who respond to immunotherapy and those who don’t? Writing in the journal Science, researchers say they may have found one reason why, in mice, at least. Dr. Kathy McCoy is one of the authors of that study, a Professor in the Cumming School of Medicine at University of Calgary in Alberta and the Director of the IMC Germ-Free Program there.
Welcome to Science Friday.
KATHY MCCOY: Hi, Ira. Thank you for having me.
IRA FLATOW: Let’s talk about your study. You took bacteria from gut tumors in mice that both respond to and didn’t respond to immunotherapy and looked at what was different in the bacteria that lived there?
KATHY MCCOY: That’s correct. First of all, we looked to see if there was a difference in the fecal microbiome, because that’s what we tend to study in humans. And then we decided to also look at if there was any difference in the types of bacteria that were associated with the tumors themselves. And we found that there seemed to be a sort of an enrichment of different types of bacteria in those tumors that were responding to this type of immunotherapy.
IRA FLATOW: When you say there was an enrichment, do you mean there was a larger population of the bacteria there?
KATHY MCCOY: They were present at a higher proportion in the tumors that were responding to immunotherapy compared to those tumors that were not responding.
IRA FLATOW: And do you have any idea what the bacteria were doing in those cancer tumors that were responding?
KATHY MCCOY: Yeah. Because we found this enrichment, we wondered if that really had any important role. So we were able to purify and isolate each of these different bacterial species. And then what we did is we put these bacterial species individually into germ-free mice so that these mice were mono-colonized with each of these individual bacterial species.
And then we tried to see if having the presence of only one bacteria would allow the immunotherapy to work in germ-free mice. We know that the immunotherapy doesn’t work at all in germ-free mice. So if you have no microbes at all, immunotherapy has no effect whatsoever.
And then what we found is that we could identify three of these bacteria that allowed the immunotherapy to work, even when only one bacteria was there. And what we identified was that these bacteria make a small molecule, or a metabolite, called inosine. And inosine was the key molecule that was helping to turn on the immune cells to enable them to be anti-tumor.
IRA FLATOW: Is it possible to replace in the mice that had cancer, to give them this inosine and then watch what happens to the tumors?
KATHY MCCOY: Yes, indeed, and that’s exactly what we did. So we know that giving them just the bacteria in their gut was able to render immunotherapy that wasn’t working and allowed it to work, not just in those tumors that were in the colon, but we also identified that it worked in other tumors that were not in the gut. And we also gave inosine, this small molecule by itself, to germ-free mice so they have no bacteria.
We gave it to them either orally so it just was in the gut, or we gave it to them systemically through an injection. And we found that both of those scenarios worked. So inosine by itself was able to turn on the immunotherapy and allow it to work to reduce the tumors.
IRA FLATOW: Wow. So this could work for many different kinds of tumors then?
KATHY MCCOY: That’s correct. And we looked at four different types of tumors in our animal models and found that it worked in all of those types. It did not work in one subtype of colorectal cancer that we tested in animals. So it looks like it works in many different types, but not all different types of tumors.
IRA FLATOW: Now, is the idea then, at least in the mice and perhaps later in people, to give them the bacteria or the inosine?
KATHY MCCOY: We’re going to try both scenarios. The bacteria we’re hoping to give maybe as a consortia of three or four different kinds of bacteria, and we would give that as a adjuvant therapy together with the immunotherapy. We would also like to investigate further the possibilities of giving this metabolite inosine by itself.
There’s one caveat about giving inosine, and what we found in our paper is that inosine itself seems to have a dual function on these immune cells that it acts on T cells. And whether it turns those T cells into anti-tumor, which would be a pro-inflammatory type of a response that you want in a tumor setting, it also can turn those T cells to be inhibitory, to turn the T cells off. And it seems that it requires a co-stimulatory signal at the same time. At the moment, we don’t know exactly what that co-stimulatory signal is, so we are wary right now of just giving inosine by itself until we can further identify what other signal is needed to ensure that we turn on that anti-tumor effect of the T cells.
IRA FLATOW: So what you’re saying is that the bacteria are supplying something else that turns the effectiveness on.
KATHY MCCOY: We believe so. We believe it’s a second signal coming from the bacteria, but it’s also possible it could be a host-derived secondary signal that we’re not sure what it is yet.
IRA FLATOW: This is amazing, because I know a lot of people are going to say, well, if it’s working in mice, why can’t we give it to people?
KATHY MCCOY: Well, we really hope to be able to translate this into humans. But it’s easier to control all of the variables when we’re working with animal models. And we really need to test the safety and efficacy of this in humans. And if we want to give the bacteria by itself, we want to be sure that this bacteria is going to get into the host, into the humans, because they’re already populated or colonized with a variety of different bacterial species. So we have to figure out the best way to administer this bacteria and to make sure that it’s safe.
IRA FLATOW: When you say they’re already colonized with bacteria, we know they have a microbiome, is the bacterium that you’re talking about, is it part of that colony that just needs to be tweaked up higher and separated? Is it something that’s already in their bodies, I guess is what I’m asking?
KATHY MCCOY: So we know that these bacteria are present in humans. We don’t know if they’re present in every human. And it may be that they have to be at a certain level to be able to provide the efficacy that we need to enhance immunotherapy. But they are known, they are commensal normal and non-pathogenic bacteria that are found in humans.
It’s possible that when people are sick, if they have cancer, that we know that their microbiome changes, and they start to lose diversity any time somebody is undergoing a chronic inflammatory disease or microbiome changes, and maybe that during those changes they start to lose the presence of these beneficial microbes. So maybe what we can do is add them back.
IRA FLATOW: What microbes– you said you had three and you were working with one, if I heard you correctly. What bacterium is that?
KATHY MCCOY: So the one that we’ve been looking at most closely is called Bifidobacterium pseudolongum. It’s usually present in the normal human microbiome at low levels, but maybe many of the listeners might recognize the name Bifidobacterium, because Bifidobacterium actually has been different species, not the one that we found, not this one called pseudolongum, but other bacteria have been identified and used in probiotics for many years.
IRA FLATOW: Yeah, I was about to say that. I’ve looked at a lot of probiotics, and I see the Bifidobacterium is on the label there. What you’re saying is not just the genus, but the species is important. It’s very targeted.
KATHY MCCOY: That’s correct. So yeah, not just the genus, but the species, even more so maybe even the strain. So even maybe different members of the pseudolongum species at different strain levels, they may also have a difference.
IRA FLATOW: You know, people listening to this are going to say, you know I take Bifidobacteria, why can’t I get that strain– can I get that strain in a pill somewhere online?
KATHY MCCOY: Right now, no, you cannot. We have to do further research to see how widespread different Bifidobacteria are that make inosine. But the one that we’ve identified so far, we have to do further research to find out how widespread it is and if it’s safe. So it’s not available on the shelf at the moment.
IRA FLATOW: You were talking about the microbiome being such a big mix of so many different bacterium. How do you even study them one at a time in the mice?
KATHY MCCOY: So that’s where you really need to have a facility like we have here at the University of Calgary, which is a germ-free facility. So we are able to breed and house mice that live, really, in bubbles. And they are born and raised without any microbiome at all. So that means no bacteria, no viruses, no fungi. And then we can isolate the bacteria that we’re interested in studying and give them back to those germ-free animals.
IRA FLATOW: How do you keep them germ-free? I’m thinking you go into the lab every day. You’re trying to study germ-free mice. How do you keep them from catching whatever bacteria are in the lab techs or on your gloves or clothing?
KATHY MCCOY: Yeah, it’s a daily challenge, but we have implemented some very strict protocols and infrastructure to allow us to keep these animals germ-free. So the animals are held inside basically a bubble, like a plastic bubble, that is fed with filtered air. And they’re fed with autoclaved sterilized food, and water, and bedding.
So everything that goes in where those animals are has been sterilized. And those bubbles are kept in a secondary bubble and then another bubble. So we really have to do a lot of protocols and cleaning to be sure that no bacteria is introduced to these animals, unless we specifically want to introduce that bacteria.
IRA FLATOW: We hear how important the microbiome is to so many body processes. I’m wondering, are the mice with no microbiome acting normal? Can you tell? Are they doing something weird? Can you tell they don’t have one?
KATHY MCCOY: Well, if you just look at them by eye, you wouldn’t be able to tell the difference. They look very normal. But if you start to study them in more detail, we know that if mice are bred without a microbiome, their immune system is very immature and also show signs of dysregulation. So they make more IgE antibodies, for example. And IgE is the antibody that helps to mediate allergic responses.
So they’re more prone to an allergic phenotype. So there are many things involved with the immune system where it is somewhat dysregulated and immature. The microbiome is absolutely required to develop a mature and regulated immune system. They also have some changes in their behavior, and you don’t really see it just when you look at the animals. But if you put them through a battery of tests that would study their behavior in response to stress or different things, they will have different behavioral outcomes as well.
IRA FLATOW: I’m Ira Flatow. And this is Science Friday from WNYC Studios. Tell me what other things beyond cancer you are using these germ-free mice to look at.
KATHY MCCOY: We are really using germ-free animals to try to understand the cross-talk between the microbiome and the immune system, and how it’s very important that you get signals from your microbiome early in life in a critical window of development so that we make sure that the immune system is developed in a regulated way, and how if you’re missing some of these critical signals in this developmental window, that has an impact on susceptibility to diseases later in life.
So we’re looking specifically at diseases like allergy and asthma, but also diseases like autoimmunity, things where we know that the immune system is very important for being regulated to make sure you don’t get autoimmunity or allergies. So those are two aspects that we’re looking at. But we’re also looking at how the brain undergoes development and how it receives signals from the microbiome in terms of no development, but also later in life in terms of no degenerative diseases, and trying to tease apart how the microbiome may be involved in that.
IRA FLATOW: We hear a lot of hype around the microbiome studies. And can you point to any true success stories in the real world where it’s really made a difference?
KATHY MCCOY: Probably the biggest success story right now is looking at fecal microbial transplantation, and that’s in the scenario of people that are infected with a pathogen called Clostridium difficile. And Clostridium difficile is a bacteria that colonizes your gut and makes toxins that can make people very, very sick. And so the gut almost becomes overrun with this presence of this bacteria. And if you take the microbiome, so basically a fecal slurry from a healthy person, and you give that to somebody who is infected with Clostridium difficile, it’s the only situation that is curative.
So more than 90% of people can be cured of their infection by fecal microbial transplantation. So the success of that has really excited researchers to see if we can use that type of therapy in multiple conditions where we know that the microbiome complexity or composition has been altered. So FMT, as it’s called, is being now used for inflammatory bowel disease studies and many other diseases.
IRA FLATOW: In the greater scheme of things, the number of people on Earth is so microscopic compared to the amount of bacteria and viruses there are on the planet. Could we be just looked at, we as humans, looked at as just a vessel for these bacteria to carry themselves around?
KATHY MCCOY: Yeah, actually, that’s a good analogy. And I like to say that we’re not actually– we’re not merely humans. We should be looking at ourselves as a superorganism, because we are never without our microbial partners.
From the moment we are born, the newborn baby enters a microbial world. And that baby starts to get colonized, and it’s a very dynamic process. And so we live with these microbial partners in very close association with our bodies throughout our life. So we’re never without them, and we would be naive to think that we are not influenced by them in any way. So we should thank them. I mean, we’re a superorganism, and they make us healthier.
IRA FLATOW: I love that. I love to talk about it in that sense. I want to thank you for taking time to be with us today.
KATHY MCCOY: You’re very welcome. Thank you for having me.
IRA FLATOW: You’re welcome. Dr. Kathy McCoy, Professor in the Cumming School of Medicine University of Calgary in Alberta and Director of the IMC Germ-Free Program there. Thanks again for being with us.