Where Leukemia Hides,
the Immune System Seeks

 

Research challenges the notion that cancer cells must contain multiple mutations to prompt an immune response.

By Erin Podolak; Photo by Peter Barta

 
 

MANY OF US HAVE PLAYED HIDE-AND-SEEK either as children or with our own kids. The basic principles of this backyard classic capture one of the central aspects of the human immune system: Our bodies are locked in a constant game of hide-and-seek. Things that might hurt us (such as viruses or cancer cells) try to hide, and the immune system seeks to find them before they cause problems.

Harnessing the power of the immune system to treat cancer has revitalized the field of immunotherapy in the last decade. However, this revolution in care has been slower to arrive in pediatrics. Drugs called checkpoint inhibitors modify the communication between cancer cells and immune cells. These drugs have helped achieve long-term success against some forms of cancer in adults but have been largely unsuccessful in children.

A mutation on a cancer cell is like posting a billboard that says, “Here I am; come get me.” Without this signal, the immune system may not as easily identify cancer cells. Like other pediatric cancers, acute lymphoblastic leukemia (ALL) does not typically harbor many mutations. Some researchers have suggested that immunotherapies may not work as well for young patients because childhood cancers have fewer genetic mutations than adult cancers.

Research by Paul Thomas, PhD, of St. Jude Immunology challenges this notion, overturning researchers’ assumptions about how ALL and the immune system communicate.

 

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Anthony Zamora, PhD (center), (from left) Paul Thomas, PhD, and Jeremy Crawford, PhD

From lab to clinic: 
“We’ve shown that it is possible for the immune system to effectively target ALL. Now, it is a matter of finding the right therapy,” says Anthony Zamora, PhD (center), who collaborated with (from left) Paul Thomas, PhD, and Jeremy Crawford, PhD, on the discovery.

Spying on the Immune System

To better understand how the immune system responds to ALL, Thomas and his team looked at specialized immune cells called CD8+ T cells. These immune cells attack cancer cells by recognizing patient-specific mutations.

Surprisingly, the researchers found that CD8+ T cells recognize 68%–86% of mutations found in pediatric ALL.

“In the game of hide-and-seek, leukemia is losing. It can’t stay hidden from the immune system; quite the opposite, in fact,” Thomas explains. “The immune system finds the leukemia, which shows us that the number of mutations present in a specific type of cancer does not necessarily dictate the ability of the immune system to recognize those cells as cancerous.”

Recently, the researchers published an article in Science Translational Medicine explaining why the immune system can recognize ALL in such high numbers. The scientists drew a comparison between the way the immune system responds to viruses and cancer.

Large viruses — like tumors that contain many mutations — have more potential targets for the immune system to detect. This leads to a process called immunodominance, where the immune system response focuses on a limited number of the most important viral targets. This process may be at work in childhood ALL, where the immune system is still focusing on the most important cancerous targets but may be relying on a greater percentage of those mutations to figure out what to attack.

 
 

In the game of hide-and-seek, leukemia is losing. It can’t stay hidden from the immune system; quite the opposite, in fact.

Paul Thomas, PhD

Hinting at a Different Treatment

Immunotherapy for pediatric cancers is just starting to take root. These types of strategies may play an important role in the future of pediatric ALL treatment, particularly for patients whose disease has relapsed, and for whom conventional therapies are ineffective. Although some investigators may have written off immunotherapies such as checkpoint inhibitors for pediatrics, Thomas and his team have now shown that these strategies could be viable.

Additional research on immunotherapy for ALL will look to identify different ways of revving up T cells to attack leukemic cells. One potential path forward for immunotherapy for ALL is through cellular therapy approaches where T cells are modified to increase the specificity and magnitude of their response.

“We’ve shown that it is possible for the immune system to effectively target ALL,” said Anthony Zamora, PhD, a postdoctoral fellow in Thomas’ laboratory. “Now, it is a matter of finding the right therapy.”

 
 

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