Immune Cells that Spot and Destroy Tumors

Gamma delta T cells, a type of immune cells, are extremely powerful at detecting and eliminating cancer cells. Patients with higher amounts of these T cells in their malignancies have a better prognosis than those with lower levels. However, scientists have struggled to grasp how gamma delta T cells spot malignant cells and how novel cancer medicines may be able to use these potent immune cells.

Gladstone Institutes and UC San Francisco researchers have now identified the circumstances that allow gamma delta T cells to recognize cancer cells. The findings were reported in the journal Nature.

“We used the power of CRISPR genome editing to get fundamental insights into what can make cancer cells recognizable to gamma delta T cells so they can be targeted for elimination,” says Alex Marson, MD, Ph.D., director of the Gladstone-UCSF Institute of Genomic Immunology and senior author of the new study. “Our work opens the door to thinking about how this pathway could eventually be targeted in future immunotherapies.”

“This study gives us crucial insight into factors operating inside cancer cells that can trigger recognition and destruction by gamma delta T cells, one of the more potent assassins of the immune system,” adds Erin J. Adams, Ph.D., professor of biochemistry and molecular biophysics at the University of Chicago, who collaborated with Marson on this study.

A cell type that has received little attention

T cells are a type of white blood cell that detects problems in the body, such as invading viruses or bacteria or cancer cells with genetic abnormalities. There are billions of T cells in your body, and each one has a protein on its surface called a T cell receptor, which identifies chemicals on target cells. Many experimental cancer treatments being researched today attempt to re-engineer T cell receptors so that T cells can target tumors more effectively.

Previous research has demonstrated that a subpopulation of T cells known as gamma delta T cells are particularly adept in detecting cancer cells across the body. However, the conditions required for gamma delta T immune cells to recognize and eliminate cancer cells remained unknown at the molecular level, making it impossible for scientists to imagine strategies to improve this process.

“We knew that gamma delta T cells recognize their target cells in a very different way from conventional T cells, but the field has had some trouble figuring out exactly how the gamma delta T cells were recognizing the cancer cells,” says Murad Mamedov, Ph.D., postdoctoral scholar at Gladstone and first author of the study.

Mamedov, Marson, and colleagues employed CRISPR technology to break hundreds of genes in lymphoma cells and examine whether gene disruptions effect whether or not gamma delta T cells kill cancer cells. They confirmed that the gamma delta T cells were identifying butyrophilins, a complex of chemicals previously demonstrated to be targeted by gamma delta T cells. These molecules, however, can be found on the surfaces of many human cells, both healthy and sick.

“In this case, it turned out that just knowing what gamma delta T cells recognize was not sufficient,” says Mamedov. “We needed to know how the butyrophilins are regulated and what makes them different in some cancer cells.”

To that purpose, the researchers confirmed another previously demonstrated fact: excessive cholesterol production, which is common in many quickly proliferating cancer cells, activated the butyrophilin complex, making it accessible to gamma delta T cells.

A stress indicator

When the researchers examined the CRISPR screen results more closely, they discovered that gene deletions that caused cellular stress and depleted energy production in cancer cells made these cells more likely to be killed by gamma delta T cells, as well as increased the amount of butyrophilin molecules on the surface of cancer cells.

Using this understanding, scientists demonstrated that when tumor cells from cancer patients are treated with a medication that mimics a cell’s stress response, these tumor cells are more easily detected by gamma delta T cells and, as a result, are killed more efficiently.

“In healthy cells, butyrophilin is invisible to gamma delta T cells, so that T cells don’t start killing them,” explains Mamedov. “But when stress pathways are increased in cancer and the butyrophilins are activated, these molecules become more abundant and act as a target for gamma delta T cells.”

While the new findings primarily shed light on the basic biology of how gamma delta T cells function and may have evolved, they also suggest that therapies that manipulate the abundance of butyrophilin on the surface of cancer cells in patients could make gamma delta T cells more effective cancer fighters.

“Much work lies ahead to design drugs that can boost cancer clearance by gamma delta T cells, but the findings of this team led by Murad move us a step closer by giving us fundamental insights into how gamma delta T cells recognize cancer targets,” says Marson.

“This amazing collaboration, which connected basic and clinical translational researchers, will allow scientists and physicians to not only better select patients for immune therapies using g9d2T cell receptors, but also to design novel compounds to enhance activity of these receptors,” says Jürgen Kuball, MD, Ph.D., one of the authors of the study, as well as professor of hematology and chair of the Department of Hematology at University Medical Center Utrecht.

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