Getting your Trinity Audio player ready...

Despite the massive successes of immunotherapy, which utilizes the body’s immune system as a tool to fight cancer, therapy resistance is still a common treatment obstacle for many patients with solid tumors.

With a new paper in the leading scientific journal Cell Metabolism, the lab of Vivek Verma, PhD, assistant professor at The Hormel Institute, University of Minnesota, outlines a pharmacological method to boost mitochondrial function in cells that could be easily translated to clinics, enhancing immunotherapy treatments for better outcomes in patients.

“This study has huge implications in reversing the resistance of cancer patients to various immunotherapies,” Verma said. “Our study provides a direct link between cell metabolism and gene expression, especially in mitochondria.”

The cancerous tumor microenvironment is a hostile one, especially to an immune cell’s powerhouse: the mitochondria. Signals given off in this microenvironment can interfere with nutrition, inhibit mitochondrial function, and lead to immune cell exhaustion. With little to no energy, immune cells are unable to actively fight off pathogens, infections, and cancerous cells. Mitochondrial function is also essential for the process of T cells transitioning from their naive phase to the effector phase—when these immune cells begin actively fighting off pathogens or cancerous cells.

Currently, there are not yet any clinically viable strategies that can be used to target mitochondria to ensure it retains the power necessary to fight off disease, including cancer.

In the Cell Metabolism paper, Verma and the team found that activating the enzyme PKM2 helped boost mitochondrial metabolism in anti-tumor CD8 T cells. Additionally, the team learned that CD8 T cells with activated PKM2 also displayed better efficacy in adoptive cell models and in combination with immune checkpoint-based immunotherapy.   

“Surprisingly, the roles of PKM2 in CD8 T cells had not yet been established. In this study, we show for the first time that pharmacological activation of PKM2 leads to mitochondria-mediated enhancement of effector functions in CD8 T cells,” Verma said. “Also surprisingly, we found that PKM2 modifies cell metabolism that regulates the expression of genes located on mitochondrial DNA. Our study provides a direct link between cell metabolism and gene expression, especially in mitochondria.”