Cells on a diet: how tweaking T-cell metabolism boosts cancer therapy
Altering T-cell metabolism during culturing could improve the effectiveness and longevity of T-cell therapies for cancer.
University of Pittsburgh (PA, USA) researchers have developed a new method of growing T cells in vitro that alters their metabolism to increases their lifespan and antitumor efficacy in a mouse model of melanoma.
T cell therapy is a treatment that involves collecting T cells from a patient or donor, expanding them in vitro, and infusing them into the patient. Unfortunately, once infused into the patient, these T cells often do not persist for very long, which limits their long-term efficacy. The team at the University of Pittsburg believed that one of the reasons for this lack of in vivo persistence has to do with the way the cells are cultured and expanded in vitro.
Current in vitro culture strategies use media with extremely high levels of glucose. The researchers suggest that these conditions don’t prepare cultured T cells for survival once they are reinfused into the body, as they then have difficulty using other energy sources and most of the cells die off quickly.
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To improve the in vivo persistence of cultured cells, the researchers added a compound called dichloroacetate (DCA) to the standard T-cell growth medium. DCA is a small molecule that alters cellular metabolism by inhibiting pyruvate dehydrogenase kinase 1. This shifts cells from relying on glycolysis (sugar metabolism) to using oxidative phosphorylation (oxygen-based energy production). Reducing the T cells dependence on glucose means they are more able to utilize other energy sources that are more common in the bloodstream.
T cells grown in media containing DCA survived longer after infusion into mice compared to cells grown in traditional culture media. One year after infusion, the researchers found that 5% of circulating T cells were those that had been reinfused. In contrast, T cells grown in traditional media were barely detectable in the mice, even just a few weeks after infusion.
In mice with melanoma, treatment with T cells grown in DCA-supplemented media resulted in improved tumor control and survival compared to those grown in traditional media. Additionally, these DCA-grown cells provided long-lasting protection as the mice were able to fight off re-exposure with melanoma cells.
These findings demonstrate the benefits of supplementing T-cell culture media with DCA and could lay the foundation for more effective T-cell therapies with prolonged efficacy, offering hope for improved cancer treatments in the future.
