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April 2, 2024

Why a New Cancer Treatment Can Lead to Autoimmunity

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. 

Peter Linsley
Peter Linsley, PhD, Principal Investigator, Linsley Lab

But checkpoint inhibitors don’t work for everyone — sometimes the wolf costume is just too good. And sometimes people develop side effects that look a lot like type 1 diabetes, overactive thyroid or other autoimmune diseases. 

BRI scientists knew that they had the team, the tools and immune system expertise to get to the bottom of this. Now, scientists from the Linsley Lab, Buckner Lab and Long Lab are working to learn who benefits from checkpoint inhibitor therapy and how autoimmune disease-like side effects develop.

“We hope to find specific biomarkers that could predict who would respond to the therapy and who would develop autoimmune disease — and to understand if one is necessary for the other,” says BRI’s Peter Linsley, PhD.

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. 

Featured Bio Ty Bottorff
Ty Bottorff, PhD

Postdocs Play a Crucial Role in BRI Science

Postdocs play a vital role in research at BRI, leading many innovative and exciting research projects as they build their careers with the mentorship of our team. When Dr. Bottorff (who uses they/he pronouns) was looking for a postdoc position, they knew they wanted to build skills in bioinformatics approaches and apply them to research questions that help people. BRI felt like the perfect place to achieve these goals.

“I chose a career in science because I was motivated by curiosity and by exploring how the world works. But I chose BRI because I wanted to do more than explore my own curiosity, I wanted to conduct science that makes a bigger impact,” they say. “This work is really exciting because it could have a clear impact on people’s lives in the foreseeable future.”

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.”

Featured Cytometer Researcher Pouring

Asking Questions in the Lab to Inform Precision Medicine

The Linsley Lab is one of many BRI labs working to drive healthcare toward precision medicine. This means a future where doctors know which medicine is best for a patient based on their unique biology, and patients get the treatments they need as quickly as possible. This research often takes key questions from the clinic back to the lab – like why do medicines work for some people, but not others? And how do we know who a medicine will or won’t work for? BRI bioinformaticians, fundamental immunologists and other experts are finding answers, making new insights and moving BRI closer to our vision of a healthy immune system for everyone.

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