Scientists have identified a promising therapeutic target that could disrupt the protective layer of sugar-derived molecules cancer cells use to evade the immune system. Results published today in Science Advances show that, under conditions of hyperglycemia, the HSF1 protein is essential for building this “invisibility cloak,” pointing to a potential new strategy to make tumors more vulnerable to immune attack.
“Our findings indicate that changes in mitochondrial function lead to the synthesis of cell surface sugar-derived molecules that make it difficult for the immune system to recognize and kill cancer cells,” said Kevin Tharp, PhD, assistant professor in the Cancer Metabolism and Microenvironment Program at the Sanford Burnham Prebys NCI-Designated Cancer Center. “Now that we know this, this creates an enormous drug discovery opportunity to take away the surface coating that protects them from immune surveillance. We think this will be a really effective strategy to attack metastatic disease and improve immunotherapy responses.”
Previous research by Tharp’s team had shown that the scar-like tissue that forms around solid tumors does more than create a physical barrier to immune cells. The stiffness of the tumor microenvironment can also reprogram the metabolism of both cancer cells and nearby immune cells, creating conditions that are hostile to an effective immune response.
“Primary tumors are typically stiffer than their surrounding tissue,” said Tharp. “This led me to hypothesize that the biophysical properties of cells influence the altered metabolic programs that everyone observes in tumors.”
A hallmark of cancer metabolism is a shift away from normal glucose oxidation within mitochondria. Tharp and colleagues investigated how two key features of the tumor microenvironment, stiffness and glucose availability, affect cancer cells. They found that both conditions, and especially glucose levels, can alter the thickness of the protective coating of sugar-derived molecules, also known as the glycocalyx.
“We observed that changing the available metabolites for those tumor cells reveals distinct biology for normal and tumor cell metabolism,” said Tharp. “We found stark separation between the glycoconjugates of cells cultured in conventional medium versus those cultured in a medium that better reflects the nutrient composition of the human body.”
Under conditions of hyperglycemia, the researchers found elevated levels of the heat shock factor 1 (HSF1) protein. Further experiments showed that cancer cells required could only boost their ability to evade the immune system when HSF1 was present, and in conditions mimicking the tumor microenvironment.
These findings point to a potential therapeutic opportunity to develop drugs that target HSF1 to thin the glycocalyx and make cancer cells more visible to the immune system. This strategy could become increasingly important as metabolic conditions associated with elevated glucose levels, such as type 2 diabetes, become more prevalent across the world.
“What we found is a plausible mechanism by which hyperglycemia directly contributes to immune evasion,” said Tharp. “And potentially a way to take away a pro-tumor advantage from hyperglycemia caused by metabolic syndrome and modern diets.”
