Tumor cells typically alter their energy metabolism and increase glucose uptake to support their rapid division and spread. This limits the availability of glucose for and therefore dampens the body’s anti-cancer immune response.
By searching for proteins that regulate cancer cell metabolism and influence immune cells in tumors, a team led by investigators at Massachusetts General Hospital (MGH) recently identified a potential target for therapies that could simultaneously divert energy from tumors and boost the immune response. against them.
For the research, which is published in Cancer Discovery, Keith T. Flaherty, MD, director of clinical research at the MGH Cancer Center and 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 cancer patients treated with immunotherapy, as well as from cell lines and animal models, the tool identified 38 immunometabolic regulators specific to cancer cells.
Artificial intelligence techniques showed that the level of activity of these regulators in tumors predicted patient outcomes after immunotherapy.
The highest identified regulator, ESRRA (Estrogen Related Receptor Alpha), was activated in many types of immunotherapy-resistant tumors. ESRAA inhibition killed tumors by suppressing energy metabolism and activating two immune mechanisms involving different types of immune cells.
Inhibition of ESRRA was safe when tested in mice, and its effects on energy metabolism targeted cancer cells.
The researchers also demonstrated that BipotentR can be applied to other survival mechanisms used by cancer cells, such as their ability to promote the formation of blood vessels to increase their blood supply.
BipotentR therefore provides a resource for discovering single drugs that can act through a single cancer-related pathway while simultaneously stimulating an immune response.
“These findings provide a simple biomarker for predicting response/non-response to immunotherapy and support ERRA as a therapeutic target,” says Flaherty.
