Meet Dr. Gregory F. Sonnenberg, One of Our New Lloyd J. Old STAR Scientists

Earlier this year, the Cancer Research Institute (CRI) launched its ambitious Lloyd J. Old STAR Program, named in honor of the “Father of Modern Tumor Immunology,” who served as CRI’s founding scientific and medical director from 1971 to 2011.

Old’s bold vision helped us build the foundation upon which immunotherapy has achieved its current success and helped transform how we think about treating cancer.  Now, to bring cures to all patients, we’ll need to venture beyond what’s already known and push the boundaries of what’s currently possible with immunotherapy. This will require taking risks, and that’s exactly what these STARS—Scientists Taking Risks—will do.

With CRI support—each STAR will receive $1.25 million over the next 5 years—these promising STARs will be exploring high-risk, high-reward ideas with the potential to produce transformative leaps forward that will enable the field’s next great advances and bring us ever closer to A Future Immune to Cancer™.

One of these promising STARs is Gregory F. Sonnenberg, PhD, of Weill Cornell Medicine in New York City, who has made a number of important contributions to our understanding of chronic inflammatory diseases and the impact bacteria within us have on the development or control of these diseases.

Currently, Dr. 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 CLIP Investigator (2019-2021).

Recently, we spoke with Dr. Sonnenberg to learn more about his work and what he hopes to accomplish during the next five years as a Lloyd J. Old STAR.

Arthur N. Brodsky, PhD:

The microbiome is a hot topic these days, and the term has appeared often in the news. So tell us, what is the microbiome?

Gregory F. Sonnenberg, PhD:

The microbiome is a consortium of micro-organisms that colonize on or inside the human body, including an estimated ten-trillion normally beneficial bacteria. To put that number in perspective, it’s roughly equal to the total number of human cells in our body. In a sense, we are as much microbe as we are human.

In addition to bacteria, there are also viruses and fungi within us as well as life forms known as protozoa. In some communities, traditional parasites could be considered part of the microbiome, too.

Arthur N. Brodsky, PhD:

With respect to bacteria, especially those that reside in our gut, we know that they can interact with tumors and the immune system. What have we learned thus far about how gut bacteria can influence immune activity as well as the development and the growth of cancer?

Gregory F. Sonnenberg, PhD:

Interestingly the microbiome was not extensively studied by the scientific community until the late 1990s, but we’ve learned a lot over the past few decades in part by studying mice that have no microbiome. For one, their immune system is dramatically impaired. They have many physiological processes that are impaired or altered. We’ve also learned that, in many disease contexts, you can transfer a human patient’s microbiome into mice and that is sufficient to augment disease progression or susceptibility, suggesting there is a major functional role of the microbiome.

In relation to cancer, specifically, this is very relevant. Historically, traditional pathogens like viruses and bacteria and their resulting infections have been linked to cancer development. We’ve known that infection can be a driver of cancer and as a result we can reduce cancers in the human population through vaccination or therapeutic control of infection.

The microbiome is not an infection, but more recently we've learned about how this consortium of microbes can dramatically impact immune responses in the context of cancer. Inappropriate immune responses against the microbiome have been found to be sufficient to provoke tumor development and tumor growth in many cases. Probably the most representative context is in the gastrointestinal tract, where specific microbes have been linked to driving the development of colorectal cancer. But it's also clear that they can affect tumors in distant sites away from the intestine as well.

Arthur N. Brodsky, PhD:

As you mentioned, bacteria can induce cancer development in some circumstances, but you’ve also found that mice without any bacteria or microbiome had their tumors grow more slowly. How do you make sense of this seeming paradox?

Gregory F. Sonnenberg, PhD:

That suggests that the microbiome also delivers a significant signal to the tumor cells themselves, or perhaps surrounding immune cells, that facilitates tumor growth and expansion. This has been something that has been appreciated in the scientific literature that I think we don't fully understand yet. Figuring out how this is happening mechanistically is another one of my goals for this project. We hope this will eventually lead to a novel treatment strategy that targets these signals to immediately slow tumor growth once detected in patients.

Arthur N. Brodsky, PhD:

I’d like to turn to bacteria and cancer immunotherapy, in particular how bacteria appear to influence the effectiveness of the PD-1/PD-L1 checkpoint inhibitor immunotherapies that have been so successful in certain cancer types. Could you talk a little bit about these new insights and what they might mean?

Gregory F. Sonnenberg, PhD:

These exciting results were generated over the past five years or so by pioneering investigators, led by Drs. Thomas Gajewski, Giorgio Trinchieri, Laurence Zitvogel, Jennifer Wargo, and Kenya Honda, among others. They found that if you got rid of the microbiome in mice, or if you supplied the mice with specific microbes, you could dramatically influence the outcome of treatment with immunotherapy as well as chemotherapy. These data suggested that the microbiome is required for effective therapy and tumor eradication in mouse models.

Subsequently, a number of these groups looked at human patients and found that antibiotics can deplete the microbiome and decrease the effectiveness of checkpoint inhibitors. Then, perhaps most excitingly, it was found that if you take microbes from patients that responded (or didn’t) to checkpoint immunotherapy, you could transfer that success (or failure) to mice, suggesting that the microbiome was really playing a significant and substantial role in controlling whether these therapies succeeded or failed. This also highlights the potential for the microbiome to explain the variable success of these therapies across individual patients or types of cancer, and also indicates that manipulating the microbiome will be a tractable target to improve immunotherapies.

Gregory Sonnenberg. Photo by René Perez. Courtesy of Weill Cornell Medicine

Arthur N. Brodsky, PhD:

Regarding the negative effects of antibiotics on treatment effectiveness, a lot of people might assume that if antibiotics are bad, then probiotics might be good. But that isn't necessarily the case, is it?

Gregory F. Sonnenberg, PhD:

Correct, there have been really intriguing data recently presented that demonstrate cancer patients who took probiotics, very unfortunately ended up doing worse in the context of checkpoint blockade immunotherapies as opposed to patients that did not take probiotics. Although preliminary, this suggested that perhaps these probiotics had a negative impact.

In contrast, I think diet could very well be one of our best ways to manipulate the microbiome at this point. It's a much more powerful way to change the composition of the microbes that are in the gut. Some work out there has indicated that eating a high fiber diet can increase the diversity of the gut microbiome, and, as a result, could potentially help improve immunotherapy’s effectiveness.

But there are vast differences between the diets of mice and humans, so we need to carefully study both ends of the spectrum and hopefully we'll be able to make good recommendations of whether you should be eating more fiber before you're getting your immunotherapies or not. I am excited to see these studies published and think they'll make a big splash when they come out.

In my opinion these results really just highlight the fundamental need to do a lot more research in this area to better understand exactly how microbes and factors such as diet are influencing cancer's response to immunotherapies. And of course, one should always speak with their physician about how certain activities or supplements might affect their response to treatment.

It's one of the important reasons to keep funding this important area of research. Unfortunately, all of us are touched in our lives by friends or family members who have cancer and it is frustrating that we cannot yet advise them on what to do in terms of manipulating their microbiome or diet to increase the likelihood of benefiting from checkpoint immunotherapies. Thankfully the science is moving fast, and hopefully will continue to move even faster in the future so that we will be able to harness the microbiome to improve existing therapies or develop novel cures to cancer.

Arthur N. Brodsky, PhD:

That’s a great point, that despite all the progress we’ve made, there is still a lot more that we don’t know, and therefore it’s extremely important to continue to invest in basic research that can help us better understand the fundamental biology at play.

I want to go back to your earlier point for a minute, regarding the observation that it’s possible to improve immunotherapy’s success in mice by taking bacteria from patients who responded to immunotherapy and transplanting that bacteria into mice. Is any approach like this being tried in humans, yet?

Gregory F. Sonnenberg, PhD:

Yes, there are several ongoing clinical trials that are taking bacteria from patients who are very good responders to checkpoint immunotherapy and delivering them—via a procedure known as fecal microbiota transplant, or FMT—to patients that are non-responders to see if we can boost checkpoint immunotherapy’s effectiveness in these patients.

But this is a crude approach and it's something we should try to improve. We want to be able to develop safer and more specific ways to manipulate how the microbiome impacts immune responses against tumors.

Arthur N. Brodsky, PhD:

Let’s now turn to one of the specific areas of focus in your research, which involves immune cells called innate lymphoid cells or ILCs. What are ILCs are, and what do we know so far about their role in immune responses against cancer?

Gregory F. Sonnenberg, PhD:

So, ILCs were just discovered about ten years ago. In terms of the immune system, they're a relatively new player that were missed for a long time. ILCs are dramatically enriched in the intestinal tract, and they respond to the microbes that colonize our gut. There is a population of ILCs that expand following birth and as your intestine is colonized with microbiome. Critically, what we and other groups found over the past decade is that these ILCs have a number of different pathways that they use to orchestrate a balance with the microbiome and maintain a state of health in the intestine.

For example, they can control how our body sees the microbiome and decides whether to mount—or limit—an immune response against the microbiome. In the context of cancer, their roles are poorly understood, and deciphering those roles is one of the main focuses of my STAR project. Currently, we have some evidence that they are present in tumors, but are fundamentally altered as compared to ILCs from healthy tissues. We are currently trying to determine what this means and whether it impacts tumor progression or responsiveness to therapies.

Arthur N. Brodsky, PhD:

Potentially, if we could better understand how these ILCs are involved in immune responses against cancer, we could target them either to stop the cancer’s growth or to make immunotherapy more effective by strengthening these immune responses. To that end, how will you be working to characterize these interactions between immune cells in the microbiome and what kind of insights do you hope to uncover?

Gregory F. Sonnenberg, PhD:

That's a great question. We're still in the very early stages of understanding these ILCs, so we need to learn a lot more about what regulates them in general and how their activity changes in the context of cancer. To do that, we’ll be using mouse models to manipulate these cells experimentally and then see how it changes the development and growth of tumors as well as their ability to metastasize, or spread to other tissues. At the same time, we want to study human populations and find out how these cells might be altered in people with cancer and what might be driving these changes.

We’re also doing translational experiments where we take the microbiome from defined patient populations and put them back into germ-free mice that are born and raised without any microbiome. Thus, when we introduce a defined human microbiome, we can see how those microbes fundamentally impact the development of the immune system, including ILCs, both normally and in the context of various cancers.

Arthur N. Brodsky, PhD:

Before we wrap up, I wanted to give you a chance to leave us with your vision for what you hope to accomplish as a Lloyd J. Old STAR grantee over the next five years and how you hope your achievements might impact the future of cancer treatment.

Gregory F. Sonnenberg, PhD:

What’s really exciting to me is that I have never had the opportunity to devote a significant portion of my lab focused on cancer-related research. We have been very focused on inflammation and immune responses to the microbiome, but we’ll now be able to take our expertise from those areas and apply them to cancer.

As a scientist focused on infectious and inflammatory diseases, I would never have been able to receive funding from traditional sources for our new foray into cancer research because those funding sources require established bodies of work in that area. Fortunately, this CRI STAR grant allows my lab to do that. It has provided a substantial level of support that makes it possible to embark on our new research trajectory.

Importantly, I think we will be able to make rapid and fundamental advances in our understanding of how the microbiome can impact tumor growth, tumor invasion, and tumor responsiveness to checkpoint blockade immunotherapies. What excites me a lot about studying the microbiome in cancer is that it is likely going to be a very tractable way to manipulate cancer growth and responses to cancer immunotherapies.

So, what we're really hoping to do over the next five years is to identify some specific therapeutic targets that we can test in the preclinical setting and then validate using patient samples to see if we can manipulate the microbiome, or the way the host interprets signals from the microbiome, to prevent, treat, or cure cancer.

Read Dr. Sonnenberg's Funding Profile

Read interviews with the CRI Lloyd J. Old STARs of 2019

• Alexander Marson, MD, PhD
• Amanda Lund, PhD
• Yvonne Chen, PhD 

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