El cáncer y la flora microbiana: el papel de las bacterias en la inmunoterapia

La flora microbiana (los billones de bacterias de la piel, las bacterias intestinales y otros organismos microscópicos que habitan nuestro cuerpo) se ha convertido en un área de investigación muy interesante en los últimos años. Los estudios sugieren que afecta tanto el desarrollo como la progresión del cáncer, así como las respuestas de los pacientes a la inmunoterapia.

En este seminario web para pacientes y cuidadores, Gregory Sonnenberg, Ph. D., de la Facultad de Medicina Weill Cornell, señala lo que se sabe hasta ahora del microbioma humano y la influencia de factores como la alimentación y los probióticos en la salud de nuestra flora intestinal. Ya se están explorando en la clínica las estrategias de tratamiento basadas en la flora microbiana para mejorar los resultados en los pacientes con cáncer. Nuestro experto se enfoca en los mayores desafíos y cuestiones que deben abordarse.

Dr. Gregory ​Sonnenberg is an associate professor of microbiology and immunology in medicine at the Weill Cornell Medical College in New York City. He also has primary appointments in the Department of Medicine and Gastroenterology Division, the Department of Microbiology and Immunology, and the Jill Robert’s Institute for Research in IBD at Cornell University. Previously, Dr. Sonnenberg completed his PhD and was a postdoctoral researcher at the University of Pennsylvania Perelman School of Medicine. He has also been a recipient of the NIH Director’s Early Independence Award, the Searle Scholar Award, the Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease Award, and has appeared on the Forbes list of rising stars transforming Science and Healthcare. He is also a CRI Lloyd J. Old STAR (2019-2024) and CRI CLIP Investigator (2019-2021).

The «Cancer Immunotherapy and You» webinar series is produced by the Cancer Research Institute and is hosted by our science writer, Arthur Brodsky, PhD The 2020 series is made possible with generous support from Bristol Myers Squibb, Foundation Medicine, and Alkermes.
 
Browse our Cancer Immunotherapy and You Webinar Series playlist on YouTube or visit the Webinars page on our website to see other webinars in this series.

WEBINAR TRANSCRIPT

Arthur Brodsky, PhD: Hello, and welcome to the Cancer Research Institute “Cancer Immunotherapy and You” Patient Webinar Series. I’m your host, Dr. Arthur Brodsky, senior science writer at the Cancer Research Institute. And during today’s webinar we’ll be discussing cancer and the microbiome, how bacteria influence our health and immunity.

Over the next 30 minutes, we’ll hear from a leading immunology expert about this exciting new area of cancer research that deals with how the billions and billions of bacteria that call our body home influence our health. In addition to aiding digestion, these bacteria play a profound role in priming and boosting our immune system.

In turn, they can impact not only the development of tumors, but also how cancers respond to treatment. That’s why we’re going to dive into the latest science of the microbiome, as well as what it tells us about how we can improve human health by rebalancing our inner bacteria.

Before we begin, I’d like to quickly thank our generous sponsors who have made this webinar series possible. Bristol-Myers Squibb, with additional support from Alkermes and Foundation Medicine. And now it is my pleasure to introduce today’s expert. Dr. Gregory Sonnenberg is an associate professor of Microbiology and Immunology and Medicine at Weill Cornell Medicine in New York City.

And last year, Dr. Sonnenberg was one of the first five scientists chosen to be funded through CRI’s prestigious new Lloyd J. Old STAR program. Thank you so much for joining us today, Dr. Sonnenberg.

Gregory Sonnenberg, PhD: Hi, Arthur. Thank you for having me. It’s a pleasure to be here.

Arthur Brodsky, PhD: So let’s jump right in. So the microbiome refers to all of the microscopic organisms that live in and on us, including viruses, some fungi, and including and perhaps most especially, the bacteria that inhabit our gastrointestinal or GI tract, in addition to our skin.

So referring to the bacteria in our GI tract, it’s fairly well known that they’re important for digestion, but what do we know about the other beneficial roles of these bacteria, especially when it comes to our immune system?

Gregory Sonnenberg, PhD: That’s a great question, Arthur. So when thinking about the microbiome and how it impacts human health, I think it’s really important to keep a number of important points in mind. Although we’ve always had our microbiome, it’s a relatively new area of research.

Scientists largely ignored the microbiome until the 1990s. However, since then there’s been a rapid appreciation for how important the microbiome can be in impacting numerous aspects of human health, beyond just aiding and helping us digest our food.

As you alluded to, these can have many diverse different roles in controlling metabolic homeostasis. They can protect us from infections and even impact very diverse functions outside of our gut, such as our functions within our brain.

Many of these diverse processes can be mediated by interactions between the microbiome and our immune system, which is also present in the gut. And to really set the stage for this discussion, it’s important to keep in mind what an astounding diversity and magnitude of microbes the microbiome is within the average human intestine.

It’s estimated that there is roughly over 10 trillion microbes. To put that in perspective, that’s roughly at a 1 to 1 ratio with the total number of cells in our entire body that are human. So really, a number of scientists argue, we are just as much microbe walking around, as we are human, given how much and how diverse this composition of microbes is that encompasses an estimated thousands of different species and different forms of life. Like you mentioned, beyond bacteria, including fungi and protists as well.

To deal with this amount of bacteria, a majority of our immune system within our whole body is actually found localized within the intestine directly. And there are a number of dynamic and reciprocal interactions between the immune system and the microbiota.

This can, in turn, support the immune system to develop and promote maturation into specific lymphoid tissues throughout the gastrointestinal tract. And this maturation of the immune system is also important in protecting us from infectious pathogens that frequently enter or colonize through our intestine.

Conversely, and the last point I’ll mention is, this interaction between the microbiome and our immune system also can promote a role in tolerance. And interactions are important in controlling and educating the immune response and telling it to not overreact and not promote inflammatory responses to things we wouldn’t want it to elicit an immune response to, such as these beneficial microbes, or food that we eat within our diet.

Arthur Brodsky, PhD: Gotcha. And I definitely want to touch on that inflammation. But first, I want to go back. It’s wild that you mentioned that there’s just as many bacteria in us as our own cells. It’s something we take for granted. We never– even scientists, for a long time, we didn’t really appreciate it.

And still, nowadays we take it for granted unless something goes wrong and it has an effect on us. You mentioned the positive things but then you also alluded to the inflammation. And I want to hone in on that, because it’s kind of the two sided coin of the microbiome.

When there’s a healthy balance in the microbiome and it’s interacting with the immune system in our tissues properly, they can promote good behaviors and keep us healthy. But if these bacterial colonies, microbiome, become unbalanced, they can promote that inflammation in the intestines that you mentioned. What are the consequences of inflammation, and can it have any effect on cancer?

Gregory Sonnenberg, PhD: Yes, that’s a great question. And as you mentioned, there’s always necessary to have a balancing act between the immune response and the microbiota. The immune response can be activated by this astounding amount of microbes constantly present in our gut.

And if that happens uncontrolled, this can drive chronic inflammatory diseases. A great example of this, and one that my laboratory works on, is inflammatory bowel disease. It also can occur in the context of food allergy if the immune response becomes overreactive to things within our diet.

And this happens when the immune response becomes really overactive. This chronic inflammation can have direct and local consequences, not only in inflammation, but also in driving cancer development and progression. And we know many patients with inflammatory bowel disease that are at a much greater risk for developing colorectal cancer, particularly if their disease is left uncontrolled and there’s continuous inflammation.

But even patients who didn’t have a history of inflammatory bowel disease and go on to develop colorectal cancer. This is also causally associated with chronic activation of inflammatory pathways in the intestine, and in large part, driven by the microbiota itself. This microbiome driven chronic inflammation can drive cancer through a number of distinct processes, including genomic instability, driving enhanced mutations, and supporting tumor invasion.

The way I think about it often and reminiscent about how chronic infections in general can be associated with cancer. It’s known that up to 15% of the worldwide cancer burden is directly driven by infections. And there’s very good examples of this in context of viruses and parasites, and even bacterial pathogens.

And it’s important to note the difference, however, between the microbiome and infection. Whereas a number of these cancers can be controlled through vaccination or hygiene practices to eliminate these pathogens, our microbiota is always with us. And you would not want to eliminate them, ever, due to their many numerous beneficial outcomes.

So understanding how the microbiome is contributing to cancer development is a very emerging area and very important to understand, how we can manipulate the microbiome to avoid this cancer progression or induction. The last thing I’ll mention, too, is this isn’t happening just locally in the gut, either.

We know that abnormal interactions between the microbiome and your immune system in the gut can have many consequences outside of your gastrointestinal tract. It’s long been known to be associated with the pathogenesis of many systemic autoimmune diseases in your airway, and your joints, in your skin, and your central nervous system.

And there’s really strong emerging evidence that these interactions between the microbiome and your immune system can impact cancer at these distal sites from the gut, as well.

Arthur Brodsky, PhD: Interesting. Yeah, I’m glad you got right where I was going to take the conversation. Yeah, that makes sense that the microbiome, because it causes inflammation and interact with our immune system and influence its diversity processes, as you mentioned, can have an influence on the development of cancer. And presumably, eventually we might be able to develop some things to help minimize, maybe, the incidence.

But especially, for right now, once a cancer is developed, obviously the impact of the microbiome, the impact the microbiome on the immune system and on inflammation and on the cancer don’t stop. So what do we know? What do we know right now about the microbiome’s impact on cancers that already developed? And does a microbiome have any influence on how someone might respond to a treatment like immunotherapy?

Gregory Sonnenberg, PhD: Yes, definitely. So there is a lot of evidence out there in the scientific community right now, that even after tumors are established, the microbiome can contribute to their growth and the progression and the responsiveness to therapies. A lot of this is driven by utilizing preclinical models in mice, for a large part, in which you can experimentally deplete the microbiome by giving mice antibiotics.

Or you can raise mice in a completely sterile environment, that’s regularly referred to as a germ free environment. Essentially living within a bubble, and never being exposed to any type of live microbial stimulation. In a lot of these contexts, it’s been found that tumors will grow at a vastly reduced rate, suggesting the microbiome is contributing through a number of distinct mechanisms, potentially in cancer growth and progression.

But the mechanisms of how this is happening and why this is happening, we don’t fully understand yet. And this is one area of active research in my lab.

Related to the immunotherapy that you brought up, that’s exactly right. And really, there was some exciting data that came out only five years or so ago, identifying that mice require the microbiome for their ability to respond to immunotherapies and chemotherapies in some contexts. With a recent notable focus on checkpoint blockade immunotherapies, like anti-PD-1 or anti-CTLA-4 therapy.

I want to acknowledge this work was done, not by myself, but by many pioneering groups, many of whom are on the CRI advisory board. Giorgio Trinchieri, Thomas Gajewski, Laurence Zitvogel Jennifer Wargo, Kenya Honda, just to name a few.

Really, they had a number of seminal studies that came out highlighting that if you didn’t have the microbiome, mice failed to respond to these immunotherapies. And importantly, mice with different compositions of their microbiomes. As you remember, I told you the microbiome contains thousands of different species. So they can have different makeups of these microbiome between mice.

These groups also found that these compositional differences can determine how well a mouse responds to immunotherapy, or whether they don’t respond at all to immunotherapy. And really, critically, what was most exciting, I think, about these data is subsequently were translated into human patients and found that as patients with different cancers that respond or do not respond to immunotherapies, having different compositions of their microbiome. And fundamentally important, the microbiome could be taken from those patients, transplanted into a mouse, and then that mouse would have a similar outcome in immunotherapy, suggesting that composition of the microbiome is, at least in part, sufficient and necessary to transmit the success or failure of immunotherapies.

And so this has been extremely exciting and opened up many more questions than answers, but provokes that we might be able to use the microbiome to improve immunotherapies for cancer patients.

Arthur Brodsky, PhD: When you describe it, it sounds like sci-fi at first. Like, it reminds me of Einstein’s spooky action at a distance. And so I want to go on. I want to unpack what you said about the bacterial transplants and how we’re using strategies to potentially help cancer patients today.

Before I do, I want to just pause a little bit on the actual– I know you mentioned that we obviously still have a lot to learn about the mechanisms of how these bacteria are influencing the immune system and cancer. But right now, and you mention also, there’s thousands of bacteria.

But right now, what does the data tell us about where these benefits to immunotherapy might be coming from? Are they linked to a certain type of bacteria? Or is it some property of the microbiome as a whole?

Gregory Sonnenberg, PhD: This is a massively important question. I’ll call it the million dollar question, of how this is happening, and also which microbes are important. As I’ve mentioned several times, there’s thousands of different species of these microbes.

And I think when these initial scientific studies were published, although many people were extremely excited about them and they massively made an impact in the scientific community, they were also met with a lot of healthy skepticism. And one reason for that was, that a lot of the microbes that were recorded to be important in these papers were different, depending on which group was studying them.

And this became even more apparent as more publications came out. Different microbe names were associated with success or failure, and not every group arrived at the same microbe. An example of this is that some of the microbe names that were found to be beneficial were, including microbes termed Bifidobacterium Akkermansia, Bacteroides.

And the short answer is, well, all evidence predicts the microbiome is fundamentally important and the composition of the microbiome is important. We still don’t really know which microbes are important or even the how and why they are important is still a big black box at this time, even though we’ve made progress.

And this shouldn’t really be too disappointing. It was very unlikely to come down to one magic bullet of a single microbe that would be important in immunotherapy, much like all other areas of microbiome research that we and many other people have worked on.

The relationship of the microbiome is likely very complex, sophisticated, and context dependent. And there might be many explanations of why we’re coming up with different microbe names. A lot of this might come down to taxonomy or how we classify and name microbes.

Scientists tend to give microbes names, but it doesn’t necessarily mean that every microbe with the same name will have the same function in immunotherapy. Or on the other hand, that every microbe with a different name will have different functions in immunotherapy.

So there could be overlapping functions or there could be cooperative actions across different consortium of microbes that we don’t yet fully understand. And finally, it is also important to not consider this only in isolation. There may be many other modifiers that might control which microbe is important in each individual patient or in each different type of tumor. That could include environment, or genetics, or other tumor intrinsic factors.

Arthur Brodsky, PhD: Gotcha. And so now, I want to, you mentioned there a little bit, it’s not about just the presence or absence of one specific type of bacteria. You have to look at the system as a whole. But I know that one of the factors I’ve seen that has popped up as– that has correlated with better outcomes for patients, is a higher diversity of gut bacteria.

And I know that some studies showed that patients who had antibiotics had a lower diversity of gut bacteria. And that was associated with worse outcomes, these less diverse bacteria. But at the same time, other studies have showed the flip side of that.

People might think, well, if in this context of cancer, obviously antibiotics are very important in a lot of context. But if you’re about to get immunotherapy, an antibiotic might not be the best thing for you. But at the same time, the flipside of that, some people might think, ‘oh, probiotics will be good because they’ll boost by my gut bacteria.’ But that’s not necessarily the case. I was wondering if you could dig into that and talk about these complexities, as far as antibiotics and probiotics.

Gregory Sonnenberg, PhD: Those are all great questions. And the frustrating part, I think, is we don’t yet know how to advise patients on how to manipulate their microbiome to have a better outcome of their immunotherapy. And you know, it’s remarkable we’re even having this conversation, I think, given that the discovery of the importance of the microbiome in cancer immunotherapies only came out five years ago.

And so the research is moving, really, at a very rapid and exciting pace. There’s a number of considerations to be made, like you raised, with antibiotics. And generally, in most disease contexts, it’s important to have a higher diversity of microbiome.

Generally, higher diversity translates to less inflammation and better outcome of host-microbiota interactions. So certainly, I think many physicians are now aware of this. While there’s an astounding number of benefits to antibiotics, I think many are considering when is the most appropriate time to administer them if needed.

Particularly in the context of individuals who might be getting immunotherapy. I know there’s many different ongoing studies of trying to figure out when the timing of antibiotics would potentially impact immunotherapy, either beneficially or detrimentally.

But unfortunately, it’s still at very early stages to be able to address this. The other important point you raised was taking probiotics. There is definitely literature out there, that actually taking a probiotic, although it’s generally thought to be a beneficial therapy in modulating the microbiome or thought to be giving us more diverse microbiome, there’s actually data emerging in a number of scientific studies that it can actually have a detrimental impact on your microbiome.

And so this term, probiotic, may not necessarily always be good. In some context, it may even potentially impair your responsiveness to therapies. But probably what we’re doing already, a number of different things that your physician would likely advise you to do, are benefiting our microbiome in ways, even though it may not be why they told you to do this. Such as adopting a healthier diet and having regular exercise, avoiding smoking and alcohol, many of these pathways are probably modifying our microbiome, that will help us fight cancer. An example of this related to the diet, decreasing red meat intake, increasing fiber, are all known to be associated with reducing cancer risk.

And I think more and more studies are going to be coming out soon that they will play a role in benefiting anti cancer therapies and, in part, by changing our microbiome. So it’s frustrating and a bit disappointing to say, certainly on my end, that we don’t yet know how to advise patients, how to change their microbiome to impact cancer immunotherapies.

But we’re making really tremendous advances. And I think this is why it’s so important to continue to support basic and translational research, so that we can get to these answers, hopefully in the near future.

Arthur Brodsky, PhD: I couldn’t agree more. I think getting that fundamental bedrock upon which we can build upon and develop new treatments, I think it will definitely be important. So throughout this time we’ve been talking about how it’s so hard to tease apart where these effects are coming from, where are these positive effects coming from?

And so now, before we have those specific answers, one of the approaches that we’re testing to help patients is what you mentioned earlier, that bacterial transplant, which goes by FMT, which stands for fecal microbiota transplant, which some people might find a pretty weird and even disgusting concept.

But now, since we can’t isolate those beneficial parts of the microbiome, until then, the solution or one of the solutions that are being investigated is to transfer the entire microbiome. I was wondering if you could explain a little bit more about how FMTs work, and especially how they’re being explored in clinical trials right now for people?

Gregory Sonnenberg, PhD: Sure. That’s a really great point. This fecal microbiota transplantation, or FMT, as you said, is one method of being able to take one individual’s microbiome and transfer it to a new individual and see if that has a beneficial role.

It has shown success in other clinical contexts. Although it’s thought to be a relatively crude method, it’s very notably effective in patients who develop Clostridium difficile infection. And one context of why individuals get this infection routinely, is a loss of this diversity in microbiota that we talked about before. And restoring this microbiome diversity with fecal microbiota transplantation is a very effective way to treat and routinely cure this infection, and it has certainly benefited a number of patients.

In terms of using this more for cancer and potentially using it to benefit immunotherapies, we don’t know. There are clinical trials ongoing. It is hopeful that doing this FMT method will provide some benefit. There are a number of questions that, again, we still don’t know the answers to. Where do we get the donor microbiota from?

Do you use, simply, a healthy individual who doesn’t have cancer? Or do you take microbiota from a cancer patient that had a big and successful response to immunotherapy and give that to a new patient and hope that their microbiota will then transmit this effective immunotherapy response?

Or even, there is discussions of, should you when you’re young and healthy, be saving samples of your own microbiome that you then might be able to utilize later on in life, if you have a loss of diversity or need a healthy microbiota transplantation. You know, hopefully, although these FMT studies will likely show some success or failure, I think the ongoing goal is to move beyond this crude method.

And as we identify more specific microbes or consortia of microbes that show promising results in preclinical models, to be able to use them more in clinical trials and deliver more selective and specific and well-defined microbial based therapies that are both safe and effective. But some of this, again, might come down to not considering this in isolation. It’s probably going to come down to which tumor types are important and other environmental modifiers that might be patient specific.

Arthur Brodsky, PhD: Absolutely. I was hoping that you could just leave us with, what are the most pressing questions in the field, and what hopes do you have for the next few years as far as some of these approaches?

Gregory Sonnenberg, PhD: Sure. I think this is a very important question of where do we go from here, now that there are some basic fundamental scientific observations. And I think there is a really good opportunity to try and move this quickly into the clinic. But before we can do that, I think we’ve said many more of these questions than answers already, of exactly how this is happening.

Which microbes are important? How are they functionally impacting immunotherapy responsiveness? And how do we transplant them and deliver them to patients to improve the effectiveness of the therapies and really fight cancer?

We’re not limited only with transfer. We talked about diet a bit, and this may be one of the most successful ways to manipulate the microbiome. The microbiome is always continuously responding to what we eat. And so there may be easy and straightforward methods to manipulate the microbiome through diet to provide the most therapeutic benefit in the context of immunotherapies.

It may also be important, I think, in the immediate future, to potentially be able to utilize the microbiome as a biomarker or predictor of which patients in advance might succeed or fail in the context of anticancer therapies, or particularly, often there can be side effects of these anticancer therapies. And the microbiome might also be an important predictor for determining which individuals might be more susceptible to these adverse outcomes, as well.

There’s also many other important areas of microbiome research. Something we didn’t have time to talk too much about today is that, particularly, cancers that impact the gastrointestinal tract, like gastric cancer, esophageal cancer, or colorectal cancer, are largely unresponsive to these revolutionary checkpoint blockade immunotherapies.

This is really surprising. And an area in my lab is regularly working on why these tumors are not responding quite as well. And you might argue, these tumors are probably likely most in direct contact with the microbiome. And so we think there could be many essential questions, that are why the microbiome is not able to support immunotherapy response in clinical benefit.

It may also be important to talk about microbiome outside of the gut as well, which we didn’t have too much time to talk about today. Certainly, the intestine contains the most, and majority of our microbiome. But there’s also microbes colonizing in many other parts of our body, like the skin, the airway, and even a recent high impact publication came out that tumors themselves, in a study of 1,500 different tumors from different individuals, can be colonized with the microbiome.

And the microbiome can be found within the tumor cells themselves, as well as within the immune cells themselves, within the tumors. So understanding where the microbiome is important and how we might be able to harness that is also fundamentally important, and could explain a lot of the variability and therapeutic responsiveness of– variability of responsiveness of tumors to different types of therapies.

Finally, I think the microbiome is probably not the only way to fight cancer and cannot act in isolation. And so it’s very important to consider this in the context of environment, lifestyle, genetics, tumor microenvironment, as we talked about. It will be important to integrate the microbiome into all of these aspects of cancer research for a broader understanding of these pathways, in order to determine how we can really effectively harness the microbiome to fight cancer.

Arthur Brodsky, PhD: That is amazing. You talked about the recent discovery, that the bacteria within tumors, that’s mindblowing. It’s so complex enough already, and then there’s this new discovery that they colonize in tumor cells, too. It really drives home how profound this area is and how much we still have to learn about it. But I’m hopeful that with people like you working on it, hopefully we can make some progress that can eventually help patients.

So thank you all for joining us today. Thank you Dr. Sonnenberg. We covered a lot and I hope our patients and caregivers found it as enlightening as I did. For more of our webinars and the additional resources we have for patients and caregivers as part of CRI’s Answer to Cancer educational programs, we encourage you to check out our website at cancerresearch.org/patients.

Here, you can read and watch stories shared by others who have received immunotherapy treatment across a wide variety of cancer types. You can register for one of our immunotherapy patient summits, browse our entire library of past webinars featuring the world’s leading immunotherapy experts, access information on other resources, including treatment, emotional support, and financial assistance. And you can help find help locating an immunotherapy clinical trial.

Finally, I’d like to thank our sponsors one last time for making this webinar series possible. Bristol-Myers Squibb, with additional support from Alkermes and Foundation Medicine.

And thank you all for your attention today. I really hope you enjoyed today’s webinar. And again, you can watch this and all of our other webinars on our website at cancerresearch.org/webinars to learn more about the immunotherapy options and research on a number of cancer types.

Dr. Sonnenberg, I just want to thank you so much again for taking the time to speak with us today, and for the amazing work that you’re doing to advance our understanding of this really, really complex relationship between bacteria and the immune system in cancer. We wish you the best of luck.

Gregory Sonnenberg, PhD: My pleasure, thank you.