Reducing cholesterol could enhance T-cell cancer immunotherapy

CLEVELAND - Cleveland Clinic researchers have demonstrated for the first time that lowering blood cholesterol levels could enhance the success of a specific type of T-cell immunotherapy in fighting cancer.

The team, led by Qing Yi, MD, PhD, of Cleveland Clinic Lerner Research Institute studied T-cell transfer, which has shown great success in recent years. Dr. Yi previously showed that a specific subset of T-cells, called Tc9 cells, have stronger anti-tumor effects than other types of T-cells. In the newly published study, they determined the mechanisms that give Tc9 cells their anti-cancer properties and how those mechanisms might be tweaked to enhance immunotherapy.

Using gene profiling, the researchers discovered that Tc9 cells had much lower levels of intracellular cholesterol than other T-cells. They hypothesized that the reduced cholesterol levels might contribute to the cells' anti-tumor effects. Indeed, when cholesterol-lowering drugs were administered to the cells, anti-cancer pathways were turned on (IL-9 expression and NF-KB signaling). Furthermore, they showed in a tumor-bearing preclinical model that reducing cholesterol levels prior to immunotherapy led to greater concentrations of IL-9 and better cancer-killing success.

Immunotherapy is a type of cancer treatment that harnesses the power of the human immune system to attack and kill cancer cells. Adoptive T-cell transfer involves transplanting T-cells engineered to recognize a certain type of cancer. Researchers have focused on many different methods to manipulate and enhance the T-cells' anti-cancer activity, such as transferring cells at different stages of differentiation or using certain drugs in tandem with immunotherapy.

"Our studies suggest a relatively simple, cost effective way to enhance T-cell transfer therapy," Dr. Yi said. "We hope to test our findings in clinical trials soon."

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Dr. Yi is Chair of the Lerner Research Institute's Department of Cancer Biology. He holds the Betsy B. de Windt Endowed Chair in Cancer Biology. Xingzhe Ma is first author on the paper, published in the Journal of Experimental Medicine.

This work was supported by grants from the National Cancer Institute (grants R01 CA163881, R01 CA200539, R01 CA211073, and R01 CA214811), the Leukemia and Lymphoma Society (grant 6469-15), and the Multiple Myeloma Research Foundation.