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Researcher studies tumor cell interaction to improve immunotherapy
Kenneth Hu, Ph.D., first got a taste of what it’s like to work in a real science lab as a senior in high school. He was part of a program that allowed seniors to work alongside doctors in a research lab.
“I was looking for an opportunity to learn about scientific research and the scientific method,” recalls Hu. “It was a great opportunity to get my feet wet in the field. And it took off from there.”
Hu fell in love with the scientific process and working with his hands. He attended the Massachusetts Institute of Technology, majoring in biology and physics. Every summer, he participated in an internship program that gave undergraduates a chance to conduct research in a lab.
“Working in the lab is really where I felt at home,” says Hu. “From then on, it was pretty obvious what I wanted to do as a career.”
Fascinated by immunology research
Hu earned his Ph.D. in biophysics from Stanford University. He’d always had an interest in immunology, and the more he learned, the more his interest grew.
“There are so many moving parts to immunology,” says Hu. “Growing up, I always had the impression that the immune system was for specific roles, like fighting off bacteria and viruses. I think what is often taught about immunology in high school is that the immune system is an army for protection.”
However, Hu learned that the abilities of the immune system go beyond fighting off foreign invaders.
“After all the visibility immunotherapy got, we began to appreciate that the immune system helps fight cancer as well,” he says. “The idea that you have a surveillance system in your body is pretty cool.”
Each of the body’s organs needs to be cleaned of old or damaged cells to function properly.
“The immune system does everything,” says Hu. “What drove me to immunology is that it’s a real balancing act. You’re always riding the line between being good at fighting off diseases like cancer, but also not hurting yourself. It’s fascinating that all of us are riding that line.”
Postdoctoral work leads to the development of new tool to study cell interactions
As a postdoctoral researcher at the University of California, San Francisco (UCSF), Hu became interested in tumor immunology. He developed a technique called ZipSeq, which allowed researchers to print barcodes on cells and map single-cell sequencing data to specific regions of tissue.
“At the time single-cell sequencing technologies were really taking off, but the problem was we were talking about tens of thousands of cells,” says Hu. “And we didn’t know where they were, relative to each other.”
ZipSeq was created with the idea of it being an analogy for assigning a ‘zip code’ to different sequences.
“If you look at a section of tissue, you can partition it into smaller regions that you’re interested in based on certain features and the cell’s zip codes,” Hu explains. “When you collect the cells, you can use that zip code to determine what region they come from as well as what region certain cells tend to gather together.”
That information informed Hu that the immune cells that were ‘communicating’ to each other were physically next to each other. This also helped him understand how gene expression changed within that population of cells. He was eager to further his research.
Enticed by MD Anderson’s research enterprise and Houston
“I knew I wanted to run my own lab, and I was thinking about where I wanted to go to start it,” says Hu, who grew up in the Houston area.
Having family in Houston made MD Anderson an attractive option for Hu to pursue a career.
“That was one of the major reasons,” says Hu. “Houston also has a great cost of living and food scene. And the size and diversity of Houston means you can find a neighborhood that suits your needs somewhere in the city.”
Hu also appreciated MD Anderson’s reputation of being the largest comprehensive cancer center in the United States.
“The sheer volume of patients and the number of cancer types that we can test here, not to mention the amount of research being done, is pretty amazing,” says Hu. “A lot of the clinical departments have a strong research wing. They do translational studies that would be difficult to do elsewhere. I knew tapping into that network of expertise would be awesome.”
Hu was also very excited about the launch of MD Anderson’s James P. Allison Institute. Named after immunotherapy pioneer James P. Allison, Ph.D., the institute is a research and innovation hub within MD Anderson that aims to bring the benefits of cancer immunotherapy to all patients.
Hu was recruited to MD Anderson through a Cancer Prevention and Research Institute of Texas (CPRIT) grant. On May 15, 2023, he officially joined MD Anderson as an assistant member of the Allison Institute and an assistant professor of Immunology.
Laying groundwork for future immunotherapy innovation
Hu is principal investigator of his lab at MD Anderson, where he’s building on the ZipSeq technology. He’s making improvements to it and incorporating it with other commercially available technologies to study cell-to-cell interactions in the tumor microenvironment.
“We want to know if there are other agents we can combine with the original immune checkpoint blockades because there are a significant number of patients whose tumors don’t respond to those checkpoint blockades,” he says. “Our goal is to understand how we’re remodeling that area. One organization of cells can lead to good responses and a different organization of cells can lead to bad responses.”
For the immune system to do its job, it relies on the cells communicating and interacting with one another.
“If you don’t have the cells in the right orientation, then you’re probably not going to get a good response,” says Hu. “We want to know if there is a way we can get the cells in a good orientation, so we can apply the checkpoint blockade to the immunotherapies we’ve already developed. By doing this, we want to make the treatment regimen stronger for cancer patients.”
While his lab’s research is focused on metastatic melanoma, they’re also beginning to study lung cancer and pancreatic cancer.
“Our hope is to generate useful tools that others can adopt and use in our field and apply to their tumor models and systems,” says Hu. “While this doesn’t necessarily lead to immediate translation to the patient, it does get the discovery engine of basic science moving faster. That’s how a lot of the most innovative immunotherapies are developed.”
How beautiful images can advance immunotherapy
They say a picture is worth 1,000 words.
In the case of MD Anderson’s immunotherapy platform, part of the James P. Allison Institute, a picture generated by spatial omics technology provides a wealth of information to bring immunotherapy to more patients.
Immune checkpoint inhibitors can treat a variety of cancers, but patients respond differently to these combination therapies based on their unique tumor microenvironment, which is made up of many cell types, including:
- tumor cells
- immune cells
- fibroblasts
- blood vessels
- other cellular components
The immunotherapy platform uses breakthrough imaging and bioinformatics tools to paint a clear picture of the tumor microenvironment before and after immunotherapy treatment. This allows clinicians and researchers to see which cell types are present within the tumor microenvironment and how the cell types change after treatment is given. These data help researchers develop more personalized strategies to target specific cell subsets and improve responses for future patients.
We spoke with Sonali Jindal, M.D., associate director of the immunotherapy platform, to understand how these beautiful images are advancing immunotherapy treatments.
What is spatial omics, and why does it matter?
Spatial omics refers to advanced molecular techniques that analyze biological molecules within their exact location in tissue samples, creating snapshots of the tumor microenvironment. This allows researchers to see the distribution of genes and proteins being expressed, different cell-states and cell-to-cell interactions at the time the sample was collected.
The tumor microenvironment is an ecosystem that includes tumor and immune cells, blood vessels, fibroblasts and signaling proteins in and around a tumor, many of which have their own unique functions and interactions with each other, creating unique cell neighborhoods. Researchers have learned that these neighborhoods can affect whether immune cells are able to recognize and attack cancer cells and influence a tumor’s resistance to treatment.
How does the immunotherapy platform utilize spatial omics?
The immunotherapy platform aims to evaluate immune responses in patients in order to understand which specific therapies or combination therapies will need to be given so that all patients can benefit from immunotherapy. Our platform collects samples, including tumor and blood samples, for immune monitoring from patients enrolled in immunotherapy studies at MD Anderson. More than 5,000 patients have enrolled from over 100 clinical studies across various cancer types.
The samples are carefully tracked and analyzed by a collaborative network of clinicians, physician-scientists and bioinformaticians who can provide real-time monitoring of patients enrolled in clinical trials. Spatial omics is a critical part of that analysis.
How do you create these beautiful images?
We use imaging to gain detailed information about the tumor microenvironment from these samples. Each unique type of cell has certain targets that can be tagged with a marker, usually an antibody or probe. These targets are stained using fluorescent dyes.
It works similar to “paint by number” instructions: each color corresponds to a specific target being studied. Advanced imaging tools then capture these colored sections, mapping out where each cell type or molecule is located.
For the last 50 to 60 years, it was only possible to color one or two markers on a given sample, which provided very basic information on a small scale. Even when researchers added up to nine color markers at a time, it still limited the amount of information that could be generated, given the complex environment.
Fortunately, we have new technology that significantly improves our depth of analysis. For example, CODEX (CO-Detection by indEXing) technology allows simultaneous image staining of dozens of proteins, cells and other targets in a single tumor sample. This technology also attaches a unique barcode to each antibody in order to track and quantify each target.
We want to make sure that we’re able to accurately detect the biologically relevant markers within the tumor microenvironment so that we can integrate all of the data to understand the cell-to-cell interactions and the interactions of specific markers. The data from these studies provide information about why some patients respond – or don’t respond – to treatment and which specific markers need to be targeted with new treatments so that immunotherapy can lead to clinical benefit for more patients.
How does the platform use these images to guide patient care?
The immunotherapy platform provides detailed datasets regarding the tumor microenvironment across thousands of patients, enabling researchers to focus in on specific cell subsets or molecular targets that may be important for the development of new therapies or the selection of specific patient groups for immunotherapy treatments.
We at the immunotherapy platform are very involved in studying each sample, with analyses of hundreds to thousands of molecular markers using various “omic” assays, to determine how cells are responding to treatments, and defining the specific cellular and biologic pathways that drive immune response to eliminate tumor cells.
This allows researchers to generate road maps of the different cellular interactions and neighborhoods involved in various types of cancer response or resistance to immunotherapy.
Generating and analyzing these comprehensive images is no easy task, but it is one that I consider paramount to my role. It is a big privilege for all of us to be able to do this at MD Anderson’s truly collaborative environment, where clinicians and researchers work together so closely. These beautiful pictures are a way to show the impact of immunotherapy so patients can see and understand what can be done for them. It’s all about helping patients. That is what the platform strives for.
Learn about research careers at MD Anderson.
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