Fine-tuning regulatory T cells to treat cancer and autoimmune diseases

Regulatory T cells, or Tregs, play a key role in modulating other cells in the immune system so they don't attack the body’s own tissues. The failure of Tregs can lead to autoimmune diseases. What's more, certain cancers take advantage of Tregs’ immunosuppressive nature to evade anti-tumor immune responses.

In a new study published in the journal Immunity, scientists at the Salk Institute for Biological Studies pinpointed genes they were able to use to fine-tune Treg activity in mouse models of cancer and inflammatory bowel disease.

“Our ultimate goal is to be able to use these genes that modulate regulatory T cells to interfere with autoimmune diseases and cancers,” Salk associate professor Ye Zheng, the study’s senior author, said in a statement.

Scientists already knew that the Foxp3 gene, which expresses its namesake protein, regulates Treg cell differentiation, maintenance and function. For example, a team from the Seattle Children’s Research Institute and the Benaroya Research Institute recently made Treg-like cells by gene editing ordinary T cells to express Foxp3 and paired them with antigen-specific T cell receptors. The engineered cells prevented harmful autoimmune response in Type 1 diabetes in mice.

Zheng and colleagues figured that understanding the mechanisms of Foxp3 expression could reveal novel therapeutic targets to alter Treg cell populations or functions in ways that could combat cancer or autoimmune diseases.

With the help of gene editing system CRISPR-Cas9, the researchers screened for genes that regulate Foxp3. They identified many Foxp3 regulators in genes encoding different subunits of SWI/SNF complex, which is a group of proteins associated with the remodeling of DNA packaging.

By using CRISPR to selectively remove SWI/SNF complex genes from Tregs, the team found that one gene called Brd9 promoted the transcription of Foxp3. Deleting Brd9 in Tregs reduced their suppressive activity in lab dishes.

“Until now, it's been very hard to fine-tune regulatory T cell activity in the body,” Eric Chin-San Loo, co-first author of the study, explained in the statement. “This complex allows us to do just that—turn up or down the activity of the immune cells but not enough to cause other forms of disease.”

To further test the effect of Brd9 on Tregs, the researchers used two different mouse models.

In mice with inflammatory bowel disease, animals that received Brd9-depleted Treg cells showed significant colitis symptoms compared with those that got control Treg cells. In contrast, in mice with colorectal cancer, transfer of the weakened Treg cells led to slower tumor growth. The researchers also discovered that CD4 and CD8 T cells infiltrated tumors at significantly higher levels.

These experiments demonstrated that controlling the vitality of Treg cells via Brd9 has potential for treating both cancer and autoimmune diseases, the team argued.

Moving forward, the researchers aim to further understand the molecular mechanisms by which Brd9 controls Foxp3. They suggest small-molecule drugs could be developed to control the activity of the ncBAF complex—where Brd9 resides—as new ways to fight cancer or autoimmune disease.