There is a frustrating truth about today’s cancer immunotherapies: while they sometimes work wonderfully to eliminate cancer completely or greatly reduce it, other times they don’t work at all.
Scientists have proposed several hypotheses to explain this mystery. It may be related to the number of genetic mutations present in the tumor, with more mutations leading to better responses to treatments. Or it may be related to the environment of the tissue surrounding the tumor, with some environments supporting an effective immune response and others inhibiting it. But so far, none of these explanations have been proven.
Researchers at Memorial Sloan Kettering Cancer Center and Baylor College of Medicine in Houston, Texas, think they have a better explanation. “It turns out that immune cells need to be distributed in a specific location to effectively kill tumor cells, and they need to be in a triangular pattern,” says Andrea Schettinger, MD, an immunologist and member of the Sloan Kettering Immunology Program.
Three-man team
You need a team of three cells, but not just any three cells. What you need, explains Dr. Schettinger, are three different immune cells working together at the same time and in the same place: one dendritic cell (the type of cell responsible for presenting parts of cancer-related proteins to T cells), one killer T cell, and one helper T cell.
These cells are not rare or unusual immunologically—they are mentioned in any immunology textbook—but until now no one knew that these cells needed to be present together in tumors to generate an effective immune response against cancer cells.
This finding, published in the journal Cancer Cell on July 8, has immediate therapeutic implications and could change the way doctors administer immunotherapies.
Evidence of immune cell failure
What intrigued Schettinger about this line of study, along with Dr. Espinosa Carrasco, a postdoctoral fellow in Schettinger’s lab and the study’s first author, was the abundant and frustrating data from human trials of adoptive T-cell therapies.
Adoptive T-cell therapies are treatments in which scientists take a sample of killer T cells from a patient, identify those that recognize cancer, make billions of copies of them in the lab and give them back to the patient. Alternatively, scientists can engineer T cells in the lab to recognize specific targets, then multiply and direct them.
The idea makes sense; it should work, but it often doesn’t. “How is it possible that we can generate perfect killer T cells in the lab and give patients billions of them and still have them fail to kill cancer?” Schettinger asks. “There seems to be something fundamentally missing about what killer T cells need to kill effectively.”
License to kill
It has long been known that killer T cells do not work alone; they need the help of helper T cells to become armed and activated. This is what Schettinger points out in the textbooks.
This is why every protocol for preparing adoptive T cell therapy adds important chemicals made by helper T cells to activate and prime the killer T cells. At this point, we believe the killer T cells are ready to fight cancer when they are reintroduced into the body.
Schittinger wonders whether killer T cells need the help of helper T cells, not only to initially become armed and activated, but also to carry out the killing mission. Do killer T cells need a license to kill?
To find out, the research team created a model of lab mice with cancer that could be treated with a type of adoptive T-cell therapy similar to the one currently used in people. They tried two different scenarios; in the first, they gave the cancer-stricken mice only killer T cells. In the second, they gave the mice both killer T cells and helper T cells. The results were clear and dramatic: Only the mice that received both types of T cells saw their tumors regress.
“What that means is that just turning on the kill mechanism is not really enough to do the actual killing,” Schettinger says. “The cells need to be given license to kill the target cell.”
How the cells get their license to kill became clearer when they looked at tumor tissue from mice under a microscope. They saw that the cells from the mice that responded to the treatment had formed the characteristic triads of immune cells, and the cells were packed together in such a way that the spatial arrangement allowed the killer T cells to finally get the message: It’s time to take action.
This was an interesting finding, but would it hold up outside of the mouse model they used?
From mice to humans
To answer this question, Schettinger and her team reached out to colleagues at Baylor College of Medicine, surgeons Dr. Hyun Sung Lee and Dr. Brian Mei Burt. The group had unpublished data on a group of patients with pleural mesothelioma, a type of lung cancer, who were treated with a type of immunotherapy called immune checkpoint blockade. Within that group, some patients responded well to the treatment, seeing their tumors shrink, while others did not.
When Baylor surgeons went back to look at the tissue samples they had collected in the trial, they found that patients who had responded to the treatment had the distinctive triads in their tumors. Those who hadn’t responded didn’t.
This was convincing evidence that immune triads are indeed important and not just a coincidence, with the three types of immune cells interacting in a way that makes them a stronger fighting force against cancer cells.
Therapeutic implications
But what are the implications of all this?
First, says Schettinger, there is potential to use these triads as a biomarker to identify individuals who are likely to respond to immunotherapy. Until now, doctors have not had good biomarkers to do this.
Second, the findings suggest that doctors should rethink how adoptive T-cell therapies are given. Instead of giving primarily killer T cells, perhaps helper T cells should be included as well, and a much smaller number of killer T cells might be sufficient if helper T cells are also in the mix.
Finally, the findings have implications for the design of cancer vaccines, where cancer-associated protein fragments are engineered to boost killer T cells in patients.
Schettinger’s team is pushing the envelope in all of these directions. For example, one of her team members, a bioengineer, is designing tools to link a single killer T cell to a single helper T cell, encouraging it to form a triad with a dendritic cell.
The team is also testing new combinations of cancer vaccines, and is collaborating with other leaders in the field to bring this work into human trials. “The main takeaway from our results is that it’s not the number of cells that matters, but their spatial distribution,” says Schettinger.