A genetic screen has revealed previously unknown regulators of Foxp3, a transcription factor that, when deactivated, may improve patient response to aggressive cancers, according to a Northwestern Medicine study published in Nature.
These newly-discovered regulators could act as “switches” to boost anti-tumor immunity, and this screening method could be used to discover other therapeutic targets for cancer and autoimmune diseases, according to Deyu Fang, PhD, the Hosmer Allen Johnson Professor of Pathology and senior author of the study.
“One regulator, Usp22, is a promising therapeutic agent against highly immunogenic cancers because its suppression not only induces tumor cell deaths, but boosts anti-tumor immunity by impairing Foxp3 regulatory T cell-mediated immune suppression functions in aggressive cancers,” said Fang, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Aggressive cancers are less sensitive to standard treatments, such as chemotherapy or radiotherapy, and have a higher chance of recurrence, creating a need for more effective treatments. Immunotherapy, which enhances the natural anti-tumor immune functions within each patient, has proved effective in some cancers, but aggressive cancers remain deadly, according to Elena Montauti, a fifth-year student in the Driskill Graduate Program in Life Sciences and co-lead author of the study.
“Although the immune system naturally has the ability to recognize and mount a defense against cancer cells, tumors can circumvent this immune attack through many mechanisms,” Montauti said.
One mechanism is the dampening of T-regulatory cells, a counterweight to other immune cells that prevent an overactive immune response. While these cells are vital for preventing auto-immunity in healthy conditions, they can hinder the effectiveness of immunotherapy — and Foxp3 is their most important regulator.
In collaboration with Alexander Marson, MD, PhD, assistant professor at the University of California, San Francisco School of Medicine, the investigators performed a pooled CRISPR-Cas9 genetic screen, inducing loss-of-function mutations in nearly 500 separate gene regulators to explore their function. One regulator, Usp22, was revealed to be critical for FoxP3 stability — in the instance where Usp22 was knocked out, Foxp3 levels were severely reduced.
Next, the investigators knocked out Usp22 in mice, but only in T-regulatory cells. This caused a modest autoimmunity but also protected against tumor growth in multiple models of cancer.
“These studies indicate that Usp22 suppression is an ideal option to promote anti-tumor immunotherapy,” Fang said.
In addition, several other promising regulators were discovered, including Atxn713 and Rnf20.
“Many of these other hits could be important regulators of T-regulatory cell function, and definitely merit further investigation,” Cortez said.
This study was supported by National Institutes of Health grants AI079056, AI108634, CA232347 and F31 CA220801-03.