Previously Unknown Pathway Allowing Cancer To Grow Unchecked Identified
Researchers have uncovered a new pathway that enables cancer cells to grow unchecked by disabling the immune system.
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A new study from MUSC Hollings Cancer Center researchers shows, for the first time, that a receptor called PPAR δ, or peroxisome proliferator-activated receptor delta, is an important player in a pathway that disables the immune system so that T-cells can’t kill cancer cells.
Led by Raymond N. DuBois, M.D., Ph.D., director of Hollings, the researchers published their findings in Cancer Research Communications.
DuBois said they used a man-made ligand, or molecule that binds to a receptor, called GW501516. It was initially developed with the expectation that it could treat conditions like diabetes and obesity but was mostly abandoned for use in such metabolic conditions because of the possibility that it could increase cancer risk.
“It binds to and activates the PPAR δ nuclear receptor. When you turn it on, it promotes cancer. It can stimulate cell proliferation and affect inflammatory pathways,” DuBois said.
“We found that it modifies the ability of the immune system to attack and kill cancer cells. So it allows the tumor cells to evade attack by the immune system.”
DuBois noted that his lab published a report 20 years ago that mice treated with GW501516 showed a dramatic increase in tumor burden.
Now, he said, this new paper “has identified a key mechanism for how that works because normally the immune cells would kill pre-cancer cells and get rid of them. Following PPAR δ activation, the immune cells lose their ability to kill cancer cells.”
This happens because when PPAR δ is activated, it suppresses the binding of transcription factor RelA to DNA, affecting NF-kappa B, a molecule that regulates immune responses.
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Subscribe for FREEThis finding opens up possibilities for researchers looking for new immunotherapy targets as they develop drugs against cancer, said first author Bo Cen, Ph.D., a research assistant professor in the DuBois Lab.
“This could present us an opportunity to target PPAR δ in immunotherapy,” Cen said.
"Although immunotherapy has had some success in certain cancer types, some patients do not respond well and, with time, actually show a resistance.”
DuBois said his lab is now working with a PPAR δ antagonist, a substance that stops an effect, to see if antagonizing the receptor leads to a fully enabled immune system.
“There's a way to turn it on and turn it off, and we will investigate whether using the drug that turns it off has a potential therapeutic impact in preclinical studies.”
Reference: Cen B, Wei J, Wang D, DuBois RN. Peroxisome proliferator-activated receptor δ suppresses the cytotoxicity of CD8+ T cells by inhibiting RelA DNA-binding activity. Cancer Res Commun. 2024;4(10):2673-2684. doi: 10.1158/2767-9764.CRC-24-0264
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