The roar of the engine. The squeal of the tires as the race car launches itself down the track. Then…the chirping of crickets—now audible because the car has sputtered to a stop well short of the finish line. What happened?

The car ran out of gas. Something similar happens to immune cells, even the ones that have been souped up by means of immunotherapy. These cells may be raring to tear through the tumor microenvironment, having had their negative regulators neutralized by immunotherapy drugs. But once these cells enter the tumor microenvironment, they conk out. They seem to run out of gas. In fact, they lose mitochondrial function and mass.

This phenomenon was studied by scientists based at the University of Pittsburgh. What they found was a kind of energy leak that could be plugged by means of clinical approaches that are already in development.

Details appeared August 2 in the journal Immunity, in an article entitled, “The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction.” The article described laboratory tests and tests with mice that suggest how the mitochondrial function of T cells can be boosted. These T cells, the University of Pittsburgh scientists reported, were better able to clear tumors.

The scientists, led by Greg M. Delgoffe, Ph.D., began by showing that T cells demonstrate persistent loss of mitochondrial function and mass when infiltrating murine and human tumors. This effect, the scientists asserted, is specific to the tumor microenvironment and not merely caused by activation. The scientists went on to collect data indicating that signals in the tumor microenvironment repress T-cell oxidative metabolism, resulting in effector cells with metabolic needs that cannot be met.

“Tumor-infiltrating T cells showed a progressive loss of PPAR-gamma coactivator 1α (PGC1α), which programs mitochondrial biogenesis, induced by chronic Akt signaling in tumor-specific T cells,” wrote the authors of the Immunity article. “Reprogramming tumor-specific T cells through enforced expression of PGC1α resulted in superior intratumoral metabolic and effector function.”

“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 the truth is that only about 20–40% of patients will respond to the treatment, and it is still unclear why,” said Dr. Delgoffe. “It's a huge question in the cancer immunotherapy field, and we think we've found a big part of the answer.”

Dr. 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  modify the T cells further so that their metabolism functions better in the tumor microenvironment.

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