PNAS: A new cancer treatment that targets the immune system's "brakes."

The human immune system has a powerful ability to defend against invaders, from viruses and bacteria to cancer cells
.
But it also has a series of checks and balances, molecular brakes, to prevent unwanted immune responses
.
In cancer patients, these "brakes" can prevent the immune system from unleashing its full potential
against tumor cells.

Now, researchers at the University of Chicago have devised a potential treatment that could inhibit the activity
of regulatory T cells.
The molecule, described in the online journal Proceedings of the National Academy of Sciences, could lead to new cancer immunotherapies
.

"We think this molecule has the potential to lift the immune veil and make the immune response more active in tumors," said
Associate Professor James LaBelle, senior co-author of the paper.

Matthew Tirrell, dean of the Pritzker School of Molecular Engineering (PME) at the University of Chicago, added: "This is a completely new and different approach to cancer treatment
.
" He is a co-senior author
of the new study.
"It's also a testament to the molecular engineering
that our researchers at PME excel at.
"

Hard-to-target cells Most immune cells trigger or perform an inflammatory response
against pathogens.
However, regulatory T cells (tregs) are the peacekeepers of the immune system and are responsible for suppressing the immune response and preventing chronic inflammation or autoimmune disease
.

For decades, scientists have known that higher levels of Treg in cancer patients are associated with shorter survival times — because Treg cells block other immune responses
against tumor cells.
However, because almost all of the molecules outside the treg cell are identical to those around other types of T cells, blocking these immune brake systems becomes complicated
.

"Unfortunately, regulatory T cells, like other immune cells, have most of the normal membrane components," LaBelle said
.
"So getting rid of regulatory T cells without blocking all the other more helpful T cells is a real challenge
.
"

With few options for drug targeting on the outside of Treg cells, LaBelle, Tirrell and their colleagues looked inside
the cells.
While developing drugs that penetrate cells is more challenging, there are more unique molecules
given the internal mechanisms of the TREG.

The researchers focused on FOX3P, a protein that acts as a transcription factor or master switch for many Treg genes, but not important
for other types of T cells.
Blocking FOX3P, by turning off these Treg genes, prevents Treg from functioning
properly.

The team knew that FOX3P molecules had to be paired to do their job; Two attached copies of FOX3P form the active protein
.
To stop this interaction, called isodimer, the researchers designed a drug that mimics a part of FOX3P called hydrocarbon nailing α-helical peptide
.
They tested dozens of versions of SAH and finally identified a SAH
that successfully destroyed FOX3P homodimers.

In a series of experiments, the team showed that the new SAH could enter T cells and effectively alter the expression levels
of all genes known to be regulated by FOX3P.
In turn, these changes reduce the activity
of TREG.

"What we've known so far is that if we can get these molecular mimics into regulatory T cells, it seems to inhibit their ability to inhibit — that's double negative," LaBelle said
.

Moving toward the clinic, LaBelle's team is continuing to work with Tirrell's lab, which specializes in developing nanoparticles, including those that can carry drugs like SAHs
.
They plan to conduct more experiments to figure out the best way to
deliver SAHs into the treg around the tumor.
They then hope to test
it in animal cancer models.

Ultimately, blocking FOX3P with SAHs may be an effective way
to inhibit treg while cancer patients receive other immunotherapies designed to boost the immune response to tumor cells.

"The next step is to package these drugs so that they can better perform the effects of
drugs in the body.
" "We want to continue to develop new iterations of these SAH, advance our understanding of how they work, and ultimately develop a product
.
"