The Microbiome and Cancer-on-a-Chip with Dr. Hyun Jung Kim

The future of cancer treatment is here for many patients, thanks to lifesaving advances in cancer immunotherapy. To bring this future to all patients, more immunological mysteries must be unraveled, including how the bacteria within us affect the activity of our immune system as well as how we respond to cancer treatment.

To that end, Hyun Jung Kim, PhD, a CRI Technology Impact Award recipient at the University of Texas at Austin, is developing a 3D cancer-on-a-chip. With this, he plans to explore how gut bacteria influence responses to immunotherapy and hopes that he may uncover important insights that may ultimately lead to improved treatment outcomes for more cancer patients.

We spoke with Dr. Kim recently to learn more about his project and his progress.

Arthur N. Brodsky, PhD:

The gut microbiota, also referred to as the gut microbiome, is a really exciting and emerging new area of research. What is the microbiome and what do we know so far about how it can affect both the immune system and cancer?

Hyun Jung Kim, PhD:

The gut microbiota is the collection of bacteria, viruses, and other microorganisms that inhabit our intestinal tract. The term microbiome technically refers to the genomes of all of these lifeforms, and it’s typically used interchangeably with microbiota. When I say gut microbiome, I’m referring primarily to the bacteria in the gut.

Several years ago it was found that different types of bacteria are linked to responses in cancer patients treated with checkpoint immunotherapy. In the pivotal initial trials, doctors collected and analyzed patients’ stool samples and found very distinct differences between those who responded and those who didn’t. Additionally, if you took these bacteria from patients who responded to immunotherapy and put them into mice, it transferred that protection and made them respond better to immunotherapy, too.

Importantly, these initial studies were done in patients with melanoma, a cancer that isn’t directly associated with the gut, yet still the bacteria appeared to impact treatment outcomes.

Arthur N. Brodsky, PhD:

That’s fascinating, how bacteria in the gut can affect how a tumor in a completely different part of the body responds to treatment. This situation seems like it would be incredibly complicated, and from what I’ve gathered, we still don’t really know much about what causes these effects. To that end, with the support of a CRI Technology Impact Award, you are building a “cancer-on-a-chip” device to study this phenomenon in depth. So, what exactly is this technology?

Hyun Jung Kim, PhD:

Yes, that’s correct, many of the details of these processes remain unknown. That’s a big reason why we’re building this cancer-on-a-chip device, which is basically a small microchip that can mimic the physiological functions and the dynamics of the human gut.

We chose to study the gut, and colorectal cancer, for multiple reasons.

First, it would be much more difficult to build a system that mimics the entire body and accounts for the gut system as well as other organs where cancer can occur. By studying colorectal cancer, we can narrow our focus to some extent on the gut environment.

Second, while immunotherapy has been relatively effective in melanoma, lung cancer, and several other types of tumors, it still doesn’t benefit the majority of patients with colorectal cancer, aside from a small subset of patients whose tumors are characterized by high microsatellite instability (MSI-H).

Regarding the chip itself, we are not trying to copy the whole complexity of the gut environment into the chip. It’s literally impossible. We’re really trying to recapitulate the key components in 3D structures, including the multiple layers of cells and tissues that make up the lining of the gut.

CRC-on-a-chip devices. Photo courtesy of Dr. Hyun Jung Kim 

This approach will make it easier for us to access and study all of the relevant cells involved in the gut environment, including tumor cells as well as gut bacteria. With this 3D structure in place containing all the different layers, we can then introduce different type of cells and bacteria, and we can monitor their crosstalk and see how they affect the immune system’s ability to potentially recognize and kill the tumor cells.

Arthur N. Brodsky, PhD:

This cancer-on-a-chip will also account for the blood vessels in our body. Why was this important to include?

Hyun Jung Kim, PhD:

We now know that successful immunotherapy responses are associated with the migration of circulating immune cells, like T cells, to the local sites of tumor growth. The power of our chip system comes from the fact that it’s a modular system that also accounts for key components of the gut and tumor microenvironments in order to mimic the physiology of colorectal cancer. And so including blood vessels is an important part of that.

Arthur N. Brodsky, PhD:

It sounds like this technology could really help advance this exciting new area of research and help us uncover important insights related to cancer immunotherapy.

Hyun Jung Kim, PhD:

We hope so. Ultimately, with this cancer-on-a-chip technology, we are seeking to characterize the relationships between bacteria, tumor cells, immune cells, and other cells in the gut. Then, we can manipulate the system to see how different factors impact outcomes in the context of colorectal cancer.

CRC-on-a-chip device with inputs. Photo courtesy of Dr. Hyun Jung Kim 

Arthur N. Brodsky, PhD:

Your technology also enables you to visualize immune responses in real time. What might the potential benefits of that be?

Hyun Jung Kim, PhD:

Typically, people use mouse models to study cancer in living organisms, but you basically have to sacrifice them for any analysis or any visualization. But now, with our transparent chip, you can just take it out of the incubator and examine it under the microscope to obtain real-time images. So you don’t have to destroy or slice samples. You can keep everything as it is and even highlight for markers of interest, such as certain cancer- and immune-related molecules.

Arthur N. Brodsky, PhD:

Additionally, traditional biopsy methods that analyze a piece of tumor, whether from mice or humans, give only a snapshot of what’s going on at one particular point in time, whereas the approach you’re taking will allow you to see how the situation changes over time, right?

Hyun Jung Kim, PhD:

Yeah, exactly. We can do longitudinal studies and examine what happens over time in all our different experimental scenarios, without having to sacrifice mice, so it’s a big difference.

CRC-on-a-chip devices. Photo courtesy of Dr. Hyun Jung Kim 

Arthur N. Brodsky, PhD:

Now, scientists and oncologists have come to appreciate how different every patient’s cancer is, how cancer is unique to each patient. It’s not “one size fits all” as it’s been treated it in the past.

Your project also really appreciates—and accounts for—the individual nature of each patient’s cancer. So you’re not just building a single generic colorectal cancer chip that is meant to represent all colorectal cancer patients. While you’ll be using the same overall chip framework, you’ll be populating it with biological samples—bacteria, immune cells, and tumor cells—from individual patients, which will enable you to examine the interplay between these different factors in the context of each person’s particular disease.

Given that it adds complexity to the work, what are the benefits of this approach? And how might it improve doctors’ ability to treat people with cancer?

Hyun Jung Kim, PhD:

Right now, checkpoint immunotherapy only works in a small fraction of colorectal cancer patients, roughly less than 15 percent. In addition, the biological differences between individuals, known as heterogeneity, are another critical challenge to develop robust new anti-cancer therapeutics. If we aren’t capturing that diversity, it will be harder to draw conclusions for a given patient.

So in part, we can use our system for doing mechanistic studies to understand the role of the microbiome, to determine the effectiveness of current immunotherapies, and to test and validate new therapeutic treatments. We’ve already found some beneficial microorganisms in the gut that can substantially decrease the expression of immune checkpoint molecules which is very, very exciting to us because we have not seen that before. Now, we can introduce immune cells and immunotherapy drugs into our system and see if these lower checkpoint levels will enable immunotherapy to be more effective.

Dr. Hyun Jung Kim with CRC-on-a-chip device. Photo courtesy of Dr. Hyun Jung Kim 

But eventually we will be able to mimic this on a chip for every single patient and create what we call personalized patient avatars. Another ongoing project of ours is focusing on how different racial and ethnic backgrounds of individual patients may be associated with particular types of bacteria, for example, as well as how that is linked to clinical outcomes. So these are some of the studies that we can do that might have real clinical impact for patients.

Arthur N. Brodsky, PhD:

How valuable has CRI’s support been for developing this technology?

Hyun Jung Kim, PhD:

The Cancer Research Institute has been amazing. My lab really appreciates CRI’s support, which has been crucial for initiating this project. We also hope to build upon it through future grants that will allow us to test and validate our ideas and implement innovative strategies that might potentially make a major impact not only with respect to our basic understanding of bacteria and immunology in the context of cancer, but also to insights that can eventually be applied in the clinic for the benefit of patients. Overall, CRI’s support has been crucial in enabling us to pursue this path.

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