An unexpected trick in a cancer textbook can fool an important component of our immune system and knock down our natural defenses against solid tumors.
Scientists from the Fred Hutchinson Cancer Center say the newly discovered vulnerability is due to improper use of T-cell types, part of a large family of blood cells that are needed for the immune system to function.
A team led by Hutch immunologist Dr. Martin Prlich, scientist Dr. Florian Mayor and Dr. Jamie Erickson published the results in Nature. They identified a subset of T cells that are found in large numbers in head and neck tumors, but not in similar oral tissues inflamed by common diseases such as gum disease.
It seems that this strange group of T cells has confused their highly specialized tasks in our immune system and is now working to protect tumor cells.
Evidence from Prlick, Meyer, and Erickson may help explain why advanced immunotherapies that work against blood cancer are less effective against solid tumors (such as breast, prostate, kidney, and colorectal cancers) that are responsible for most deaths from cancer. Researchers say it points the way for future drugs that could deprive it of that protection, making modern treatments better for more people.
“Ironically, this is not what we were trying to do,” Prlic said. “We were just interested in how the tumor environment differs from normal inflammation. It was as if you weren’t looking for treasure and then you came across what many others were looking for. “
New techniques reveal an unnoticed feature of T cells
The discovery came after Hutch’s team developed new methods for analyzing cells in inflamed tissues and applied sophisticated computer analysis to their research. They compared the types of immune cells found in and around patients ’head and neck tumors with those that appeared in tissue samples from patients treated for gum disease.
As they suspected, the tumor-responsive immune cells were very similar to the cells in inflamed gum tissue – until they looked more closely at their data and found a striking difference in one type of T cell taken from a cancer sample.
T cells perform various tasks in the immune system. One of the most important is to trigger an inflammatory response, a coordinated attack to destroy cells damaged by infectious agents or cancer. Crowds of T cells are doing much of this by killing themselves.
Other types of T cells work to soothe their overactive counterparts. Known as regulatory T cells, or T-reggae, they usually stop inflammation by calming this crowd and thus protecting nearby healthy tissues. Without enough T-regs, people can be vulnerable to uncontrolled abuse of their own immune systems, suffering from autoimmune diseases such as lupus or rheumatoid arthritis.
What Prlic and his colleagues found was a different shade of T-regs. These immunosuppressive cells, which are thrown into tumor medium samples, were different from T-regs found elsewhere in the body. The surface of their cells is marked by two separate protein receptors. These specially labeled T-reggae were particularly good at eliminating inflammation, increasing the number, and protecting tumor cells from attack by other T-cell types.
“A very large proportion of these critical immunosuppressive cells in tumors have this trait,” said Meyer, who began research with Erickson five years ago. “You don’t see this in T-regs circulating in the blood, while in tumors we see that up to 75% of T-regs produce these receptors.”
To the casual observer, T-reggae from tumor samples will look nothing like those found elsewhere on the body. But the team used new techniques that allow scientists to identify the characteristics of tens of thousands of individual cells in the sample, and advanced computational techniques to sift through the data. This allowed them to detect two types of receptor proteins on the surface of T-regs collected from the tumor. Subject proteins have names that only a scientist can love: IL-1R1 and ICOS.
“What makes these cells unique is what they express [display] both of these proteins, “Prlic said.” You just don’t see co-expression on other T-reg cells. “
Once this duo of molecular-scale markers was discovered, the researchers realized that the T-regs that carry them would be easy to detect with a simple test – antibodies that bind to the markers and carry a fluorescent label.
Once a cancer trick is detected it could be undone
One of the reasons researchers have not previously noticed this pair of proteins is that they are found in human T-reg and not in mice. Much of the laboratory work in immunology relies on murine “models” of the immune response, but this study focused on human tissues taken from patients who had cancer or non-cancerous lesions.
“It doesn’t detract from the importance of mouse models. It just emphasizes that we also need to study human tumor tissue so we don’t miss things like that,” Prlic said.
These human-associated T-reggae were collected in the thickets of blood and connective tissue cells in and around the malignant mass – the site of a biological area known as the tumor microenvironment. And because these cells are easy to spot, theoretically they can also be easily targeted by anticancer drugs.
“Suddenly now we have a way to specifically target T-regs that only appear in tumors, and previously that was impossible,” Prlic said.
Prlich and his team believe that these T-reg residents living in the tumors were tricked by cancer into working for the wrong team. In an environment of T cells seeking cancer cells for destruction, tumors have acquired the ability to attract or create a blanket of these T-reg-bearing ICOS / IL-1R1. How exactly they did this is not clear, but their action is to create an “immunosuppressive” environment by protecting the tumor from normal T cells doing their job.
While the study focused on head and neck tumors, Meyer, Erickson and Prlich believe their discovery may be important for many cancers. Once they learned that the presence of these markers was important, Hutch researchers scanned a database of genes activated in samples representing 21 different types of cancer. Looking only for a gene that encodes the rarer protein IL-1R1, they saw that it appeared at different levels among all 19 types of solid tumor cancer, but not in the other two that were blood cancers.
If the drug can be designed to knock out only T-reggae in tumors but does not harm these immunosuppressive cells elsewhere, this may be an effective way to disable protection against solid tumors. If fraudulent immune cells can be eradicated, cancer-fighting T cells will be able to attack the tumor, while conventional T-regs can do their job – preventing inflammation from damaging healthy tissues.
Prlic and his colleagues hope to develop “bispecific” antibodies – one that can capture two different molecular targets simultaneously. In this case, one arm of the Y-shaped antibody protein would bind to the ICOS receptor; the other hand would capture the IL-1R1 receptor.
The goal of bispecific antibodies would be to disable or label for destruction all resident T-reggae tumors without harming these cells, which soothe inflammation elsewhere in the body. Previous efforts by drug developers to target T-regs have been unsuccessful because they lacked the precision to destroy only T-regs that protect against tumors.
Now scientists may have a way to target only T-reggae that have been tricked into protecting tumors, possibly releasing the rest of the immune system to do its job.