Activating Fat-Burning Gene Helps Immune Cells Fight CRC

A transcription factor that typically helps cancer cells grow can be redirected to help immune cells fight cancer instead, according to new research from Cold Spring Harbor Laboratory (CSHL) published in Nature Immunology. The finding targets a problem with few good solutions: colorectal cancer, now the leading cause of cancer-related death in people under 50, whose most common forms generally don’t respond to chemotherapy or newer immunotherapy drugs. 

The work centers on peroxisome proliferator-activated receptor delta (PPARD), a transcription factor that helps orchestrate fat burning inside human cells. Senior author Semir Beyaz and his lab started from an idea about fitness, broadly defined. “We hypothesized that the fitness determinants of cancer and our immune cells may not be so different,” Beyaz said. “They’re in the same universe. They’re constrained by the same chemical and physical rules. So, it’s not surprising they’d end up evolving the same way.”

Working first in a mouse model of colorectal cancer, the team found that while cancer cells carry their own PPARD, activating PPARD on the immune side instead converts a tumor environment that favors cancer into one that favors the immune system. “It’s all about cell fitness,” Beyaz explains. “What cells eat affects who they are. When immune cells burn more fat, they become more fit for fighting cancer.”

To test whether this translated to human disease, the lab activated PPARD in CAR T cells, a type of synthetic immune cell already used in some cancer immunotherapies, and tested them against organoids grown from patient tumor tissue, against human cancer cells in a dish, and against human cancer cells implanted in mice. In each setting, the PPARD-activated CAR T cells slowed or stopped tumor growth. Although the team initially focused on colorectal cancer because of its toll on young people, they validated the approach in breast cancer, ovarian cancer, and melanoma as well. Beyaz calls the findings the “tip of the iceberg” for making cancer immunotherapy more effective. 

The approach may extend beyond cancer. “Boosting immune cell fitness may also help with other conditions where the immune system fails to clear diseased cells,” Beyaz says. His lab is now testing the strategy against endometriosis, a chronic inflammatory disease that affects one in 10 women and, like colorectal cancer, has no effective treatment.