Picture this: Immune cells called T cells zoom around the body looking for threats like viruses, bacteria and cancer cells to fight off. They sometimes come across tiny features on the surface of healthy cells called checkpoints. These checkpoints tell T cells “I’m a healthy cell, don’t attack me!”

Cancer cells have learned to hide in plain sight — like a wolf in sheep’s clothing — mimicking these checkpoints. T cells zoom by, leaving the cancer cells alone and allowing them to spread.

A new cancer therapy called checkpoint inhibitors aims to stop this by revealing the wolf under the wool and blocking checkpoints on cancer cells. This mobilizes T cells to move in and attack. Checkpoint inhibitors have given new hope to people with cancers like melanoma, lung, and bladder cancer, offering the promise of a more targeted treatment that’s less toxic than chemotherapy and radiation. 

Ramping Up the Immune System

The autoimmune disease-like symptoms some patients experienced after checkpoint inhibitor therapy baffled some people. But not Dr. Linsley. 

“I would have been more surprised if it didn’t happen,” Dr. Linsley says. “The immune system is like a continuum. On one end, it’s underactive and people get cancer. Go too far the other way, it’s overactive and we start to see autoimmune disease. Checkpoint inhibitor treatment ramps up the immune system to fight cancer, so it makes sense that it might become too active and cause autoimmune disease-like symptoms.” 

Some patients only had mild side effects. Many people who experienced side effects actually had a stronger antitumor response, meaning their body did a better job of fighting off the cancer. But for a small number of people, the side effects were so severe that they had to stop treatment.

“Right now, there’s no way of knowing what response a person will have, so we hope examining this in the lab can generate data to help clinicians make the best decisions for their patients,” says Ty Bottorff, PhD, a postdoctoral researcher focused on bioinformatics in the Linsley Lab. 
 

New Insights from Bioinformatics

Drs. Linsley and Bottorff are examining blood from people receiving checkpoint inhibitor therapy. Dr. Bottorff uses some of the latest approaches in bioinformatics, a field that applies advanced tools in computer science to find meaningful patterns in biological data. The lab team is zeroing in on specific sequences of proteins inside T cells to better understand when and why they decide to attack.

Their efforts have already revealed a unique and very specific group of T cells. These T cells seem to be cross reactive, meaning they are attacking both the cancer and healthy cells. 

“We’re now taking a closer look at this very specialized subset of cells and asking why they decide to react with tumors? What is it about them that’s different?” Dr. Linsley says. “These cells could help us predict things like who is a good candidate for checkpoint inhibitors and what kind of side effects they might experience.”