Scientists Identify Protein That's Crucial to Tumor Cells' Metabolism and Immune Evasion

BOSTON – Tumor cells typically alter their energy metabolism and increase glucose uptake to support their rapid division and spread. This limits glucose availability for immune cells and therefore dampens the body’s anti-cancer immune response.

By searching for proteins that both regulate the metabolism of cancer cells and affect immune cells in tumors, a team led by investigators at Massachusetts General Hospital (MGH) recently identified a potential target for therapies that could simultaneously drain tumors of energy and boost the immune response against them.

For the research, which is published in Cancer Discovery, Keith T. Flaherty, MD, the director of Clinical Research at the MGH Cancer Center and a professor of medicine at Harvard Medical School, and his colleagues developed a new computational tool called BipotentR that can identify targets that block immune activation and also stimulate a second user-defined pathway (in this case, metabolism).

When applied to gene expression data from patients with cancer who were treated with immunotherapy, as well as from cell lines and animal models, the tool identified 38 cancer cell–specific immune-metabolic regulators.

Artificial intelligence techniques showed that the activity level of these regulators in tumors predicted patients’ outcomes after receiving immunotherapy.

The topmost identified regulator, ESRRA (Estrogen Related Receptor Alpha), was activated in immunotherapy-resistant tumors of many types. Inhibiting ESRAA killed tumors by suppressing energy metabolism and activating two immune mechanisms involving different types of immune cells.

ESRRA inhibition was safe when tested in mice, and its effects on energy metabolism were focused on cancer cells.

The scientists also demonstrated that BipotentR can be applied to other survival mechanisms used by cancer cells, such as their ability to promote blood vessel formation to increase their blood supply.

Therefore, BipotentR, available at http://bipotentr.dfci.harvard.edu, provides a resource for discovering single drugs that can act through one cancer-related pathway while simultaneously stimulating an immune response.

“These findings provide a simple biomarker to predict response/non-response to immunotherapy, and they support ERRA as a therapeutic target,” says Flaherty.

Additional MGH co-authors include Phillip Munson, Dejan Juric, and David E. Fisher.

This work was supported by the Adelson Medical Research Foundation.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.