Dr. J.C. Villasboas studies the interactions between the patient immune system and cancer cells, using advanced single-cell imaging technology. He also directs the Mayo Clinic Immune Monitoring Core Facility, which is a shared resource for all Mayo researchers to access technologies to study the immune system.
In a recent podcast interview on Mendelspod , Dr. Villasboas spoke about his work on the Cancer Immunome Project, an effort by Mayo Clinic researchers to map the human immune system. His team is applying spatial biology approaches to comprehensively describe the dynamics of the immune landscape in cancer patients.
The gap in cancer research
Dr. Villasboas believes that the future of cancer research will be largely built upon our discoveries around cancer immunotherapy. Developing strategies to help the patient’s immune system fight off cancer requires biomarkers to select the right therapy for each patient.
“We’re no longer talking about one molecule, one target. We’re talking about one or more molecules in a whole complex biological system,” says Dr. Villasboas. The way we predict response needs to match that complexity.
Checkpoint inhibitors have revolutionized cancer therapy and helped many patients over the past few years. Yet, we still lack a reliable and robust biomarker to predict patients who are more likely to benefit from these therapies. “Everyone knows that you can’t just rely on PD-L1 IHC staining,” says Dr. Villasboas.
The Mayo Clinic team is trying to close this gap by developing a catalog of the human immune system. The Cancer Immunome Project focuses on describing the immune system of cancer patients at the highest level of detail.
The project is enabled through a combination of single-cell cytometry and single-cell imaging in a very rich and clinically annotated cohort from the Mayo Clinic population. This allows researchers to look into multiple kinds of cancer, including different rare types, at different stages, to try to understand the dynamics of the immune system in those groups of patients.
We’re talking about one or more molecules in a whole complex biological system.
The Cancer Immunome Project seeks to describe these immune interactions at both the systemic level — through mass cytometry analysis of peripheral blood, and the local level — through single-cell, multiplex immunofluorescence-based imaging of the tumor microenvironment.
Applying spatial context to the cancer immunome
The immune system is naturally complex. In order to fully characterize the different immune populations, two or three markers won’t be enough, according to Dr. Villasboas. Instead, we need a series of markers that, when put together, are able to determine the role of the immune cell in the broader context of the immune microenvironment.
“Context, in immunology, is everything,” says Dr. Villasboas. The position of a cell in the tumor microenvironment can have important implications for its function and relationship with other cells. An immune cell that is in direct contact with a tumor might be providing growth factors to promote tumor growth instead of attacking it. By taking into account both the proteins expressed on the surface of the cell, but also the position of the cell in relation to the tumor and other immune cells, it is possible to study the full breadth and depth of the immune system’s complexity.
Analyzing a peripheral blood sample provides bulk data from all nucleated cells. It doesn’t tell you if a mutation or epigenetic regulation being detected is coming from the tumor compartment versus the normal immune system compartment, says Dr. Villasboas. It’s single-cell, spatial technologies that get us close to that answer.
Context, in immunology, is everything.
When you analyze tissue with single-plex IHC, you go into it with a bias, says Dr. Villasboas. You might stain for CD3 because you expect to see it expressed in T cells. While this may be valid, you also lose the opportunity to discover something unexpected. A highly multiplexed panel gives investigators the ability to find more cell populations, including novel cell populations with unexpected expression patterns.
The Cancer Immunome Project uses the CODEX system for single-cell imaging. Right now, says Dr. Villasboas, they’ve developed a panel which easily analyzes over 23 proteins from a single 8 μm tumor section. Without CODEX, gathering that level of information would have required 23 different tissue sections — often an impossibility, especially when working with clinical samples. “One single stain does not compare with the ability of actually measuring all of them, at the same time, on the same section,” he says. With CODEX, it’s possible to truly co-localize these proteins, instead of relying on software that overlaps images for a rough approximation.
Through spatial biology, Dr. Villasboas’ team is developing a comprehensive map of the cancer immunome. With a better understanding of the immune landscape and how it differs between patients, we will be better equipped to develop immunotherapies and match them to the right patients.
Interested in learning more? Listen to Dr. Villasboas’ interview on Mendelspod.