Immune Cell Discovery Clears Way for Cancer Immunotherapy Strategies

Issue Date: 
August 22, 2016

The cellular environment that supports a cancerous tumor also starves the immune cells the body sends to destroy the cancer, according to new research from the University of Pittsburgh Cancer Institute (UPCI). The discovery holds the potential to significantly boost the performance of breakthrough immunotherapy drugs.

Greg M. DelgoffeThe UPCI team looked at what happens when the immune system’s T cells enter the cellular environment surrounding the tumor, known as the tumor microenvironment. The researchers found that in this microenvironment, the T cells’ mitochondria—the cells’ energy producers—begin to shrink and disappear, indicating that the T cell is out of fuel and can’t do its tumor-destroying job. The finding, reported recently in the journal Immunity, opens the door to several potential clinical approaches that could help keep T cells functioning and boost the body’s ability to fight cancer. 

“Immunotherapy to stimulate the body’s immune system has increasingly become the way we treat people with aggressive cancers. It’s effective for a subset of patients, but only about 20 to 40 percent of patients will respond to the treatment, and it is still unclear why,” said senior author Greg M. Delgoffe, an assistant professor of immunology in the School of Medicine and member of the Tumor Microenvironment Center at UPCI. “It’s a huge question in the cancer immunotherapy field, and we think we’ve found a big part of the answer.”

As tumors grow, they build a microenvironment, which develops its own blood supply and keeps the tumor thriving, protected, and voraciously consuming all available nutrients.

When T cells enter the microenvironment, it’s as if they’re “automobiles that suddenly had the emergency brake applied; they can’t keep driving,” Delgoffe said. Immunotherapies take these brakes off. “However, what we’re discovering in many cases is that even though the brakes have been taken off, there isn’t any fuel in the tank,” Delgoffe said. Or—in scientific terms—the lack of mitochondria in the tumor-infiltrating T cells keeps them from functioning.

“This is an exciting discovery because we already have various strategies to ‘fill the fuel tank’ and support T cell function in the tumor microenvironment,” he added.

In laboratory experiments and tests with mice, Delgoffe and his team found that when they boosted the mitochondria in the T cells, they were better able to clear the tumor. 

Delgoffe is partnering with other scientists to test various mitochondria-boosting strategies, including using drugs that already have proven safe in humans, such as those for type 2 diabetes, to stimulate T cell metabolism. He’s also working with existing immunotherapy studies to further modify the T cells so that their metabolism functions better in the tumor microenvironment.