New research from Memorial Sloan Kettering Cancer Center (MSK) finds a potential therapeutic opportunity in regulatory T cells' resilience to the loss of Foxp3; shows how cancer develops resistance to antibody-drug conjugates; develops a new system to help make gene editing safer and more reliable; and shows provider billing margin doesn't drive cancer treatment selection.
Resilience of mature Tregs in the face of Foxp3 loss suggests therapeutic opportunity
Regulatory T cells (Tregs) serve as the immune system's "brakes," keeping damaging inflammation in check. And the transcription factor Foxp3 has been shown to be essential for establishing this role.
Now, using a novel mouse model that allows for the selective degradation of the Foxp3 protein, MSK researchers showed that Foxp3 is more context-dependent than previously understood. It's critical for newborn mice — without it, they develop severe autoimmune disease. But in healthy adult mice, degrading Foxp3 in mature Tregs led to only minor changes. Further experiments showed this resilience in mature cells takes several weeks to develop.
In other words, context matters — and this could be especially helpful in the context of cancer, the researchers note.
Under stress, such as rapid cell division or severe inflammation, loss of Foxp3 has more profound effects. When the scientists degraded Foxp3 in adult mice with cancer, their tumors stopped growing and shrank. That's because dampening Foxp3 impaired the function of Tregs inside tumors, releasing the brakes and allowing immune cells to better attack the cancer — while largely preserving Treg function outside of the tumor, therefore, avoiding severe adverse effects.
"This opens a potential path towards novel cancer immunotherapies employing Foxp3 degraders to inactivate highly activated regulatory T cells, which support tumor progression, while avoiding debilitating autoimmunity," says senior study author Alexander Rudensky, PhD , who chairs the Immunology Program at MSK's Sloan Kettering Institute .
The study was led by first author Wei Hu, PhD , a research fellow in the Rudensky Lab. She is now an assistant professor of immunobiology at Yale University.
