NOV 29, 2022 6:00 PM PST

Kicking Pro-tumor Immune Cells Out of the Microenvironment

WRITTEN BY: Amielle Moreno

To be a successful tumor, avoiding destruction by immune cells is a top priority. One clever way to achieve this goal is to befriend your local T regulatory cells. T regulatory cells (Treg) suppress the immune response of other T cells. They’re critical for autoimmunity prevention, while influencing other T cell proliferation and cytokine production.

regulatory T cell

Image Credit: NIAID, via Creative Commons license CC BY 2.0, no alterations made.

By making the tumor microenvironment (TME) Treg-friendly, tumors essentially use the immune system against itself. The high number of Treg cells in the TME ward off effector T cells (Teff) and their antitumor effects. This is how intratumoral T regulatory cells (itTreg) act as pro-tumor agents. But how can you decrease itTreg activity without risking an autoimmune response?

In a new paper out of Science Advances, Northwestern University’s Fang laboratory accomplished this hat trick by targeting itTreg cell’s transcription factor forkhead box P3 (Foxp3). This protein is essential for itTreg cell’s enhanced TME fitness. Foxp3’s Achilles heel is ubiquitination.

Ubiquitin-specific peptidase enzymes (USP) Usp21 and Usp22 encourage Foxp3 transcription and stabilize the FOXP3 protein. These USPs are upregulated in the hypoxic, low glucose, TGF-Beta filled, and amino acid deprived TME. Enhanced UPS activity in the TME leads to increased FOXP3 stability and allows itTreg cells to hang around tumors, suppressing antitumor immune response.

The authors developed the first inhibitor designed to suppress antitumor activities of Treg via the Usp22 enzyme. Application of a small molecule Usp22-specific inhibitor enhanced antitumor immunity. By targeting the enzyme stabilizing Foxp3 and its protein’s deubiquitination, the authors essentially eliminated the advantage Treg cells have in the TME. By making the TME less friendly to itTreg cells, Teff cells were free to display their antitumor effects.

The treatment successfully targeted Treg cells with little effect on other immune cells or damage to healthy tissue. This approach has great therapeutic potential and could work in tandem with other anticancer immunotherapies. USP targeting could “increase response rates and overall survival across cancer types” in clinical settings.

 

Sources: Science

About the Author
Doctorate (PhD)
Amielle Moreno earned her doctorate in neuroscience from Emory University and has dedicated her career to science communication, news coverage, and academic writing/editing. She is a published researcher who has branched out to author articles for various science websites. She is currently preparing a second academic manuscript for submission. It will detail her findings on how sensory areas of the brain respond to social sound. When she's not writing or editing, you can find her spinning the latest neuroscience news into comedy gold, hosting her podcast "Miss Behavior Journal Club." This fortnightly humorous podcast features the latest in behavioral research. Her goal in life is to defend and discover scientific truths.
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