What was initially regarded as a botched experiment in a lab from the Medical University of South Carolina became a surprising discovery and a new way to enhance the immune system’s ability to kill tumor cells. The new study is published in JCI Insight.
Associate professor of immunology Chrystal M. Paulos, PhD, thought that by inhibiting two molecules involved in pathways thought to play a role in improving T cell responses, she could show how the two molecules were involved in cancer immunity. The results of her study certainly indicated the two molecules, β-catenin and p110δ, to be involved in cancer immunity, but not at all in the way she expected.
β-catenin and p110δ inhibitors suppress the activity of two ICOS-induced pathways. ICOS, or “inducible T cell costimulator,” is a protein that works in several ways to enhance T cell responses. T cells are responsible for attacking foreign and abnormal invaders, including tumors, so it is clear why Paulos was surprised when inhibiting β-catenin and p110δ actually improved the anticancer ability of T cells instead of hindering it.
The new finding could be an improvement to an existing immunotherapy called adoptive T cell therapy (ACT), which is designed to treat cancer with the extraction, enhancement, and reinfusion of T cells.
“We might be able to overcome some of the delays and disadvantages of rapid expansion in the laboratory," explained Paulos, senior author of the new study. "We might be able to use fewer cells (for ACT) because we can pharmaceutically 'juice' these T cells to make them more fit in the oppressive tumor microenvironment."
After extraction and before reinfusion, T cells are enhanced to better fight cancer and rapidly expanded into an army. However, rapid expansion weakens the T cells, and they often do not live very long after reinfusion. Paulos’s new approach, though, has been shown to improve T cell potency, function, and stem-like flexibility. As an added bonus, the approach reduces the number of regulatory T cells in the tumor microenvironment; high levels of regulatory cells can inhibit T cell activity.
"We know that T cells used for ACT age and wear out over time. Somehow these drugs sustain their youth and function,” Paulos said. “They're able to keep all the properties of their youth-they expand better and they're more functional and handle the oppressive tumor microenvironment better."
Inhibiting β-catenin and p110δ inhibitors could also help T cell anticancer abilities in the context of other types of immunotherapy, including checkpoint inhibitors and vaccine approaches. For now, the study is especially promising because β-catenin and p110δ inhibitors are already approved by the U.S. Food and Drug Administration.
"From a clinical standpoint, this finding indicates that the therapeutic effectiveness of ACT could be improved by simple treatments with readily available drugs,” Paulos explained. “It opens a lot of new investigative avenues for next-generation immunotherapy trials.”
Source: Nature, Medical University of South Carolina
