The investigators compared samples of the patients' tumors and blood from before and after the cholesterol-lowering intervention. They found that the intervention limited the signaling of the mTOR complex 2 (mTORC2) protein in CD8+ lymphocytes, which are immune cells that Kim called "the primary workhorse" of the adaptive immune system.
The mTORC2 protein is important to cell growth, but the connection between mTORC2 and cholesterol hadn't been established until this study, Kim said. With the patients' cholesterol lowered and mTORC2 signaling reduced, their CD8+ cells—which have memory that allows them to recognize invading pathogens and cancers—were able to invade their prostate cancer tumors and reduce the tumors' growth.
The researchers traced this cause-and-effect relationship in greater detail through experiments in laboratory mice with prostate tumors.
Investigators knocked out mTORC2 signaling in the immune cells of mice that did not receive cholesterol-lowering therapy, and they found that these mice saw the same tumor-inhibiting benefits as mice that had received cholesterol-lowering therapy. This established that the cholesterol-lowering therapy works through this pathway.
To confirm that it was the CD8+ immune cells attacking the tumors, investigators transferred these cells from mice that had received cholesterol-lowering therapy into mice that had not. The cells acted against the tumors, slowing their growth. And when investigators depleted CD8+ immune cells in mice that had received cholesterol-lowering therapy, their tumors grew as if they had received no treatment.
"We showed in these animal models that lowering cholesterol decreases tumor growth through the immune system, which is a new observation," said Kim, who is also a professor of Surgery, the director of the Academic Urology Program, and the Homer and Gloria Harvey Family Chair in Urologic Oncology in honor of Stuart Friedman, MD, at Cedars-Sinai. "We have parallel studies in humans and mice and have been able to identify a fairly detailed mechanism by which this happens: Serum cholesterol goes down, mTORC2 signaling goes down, immune cells move into the tumor and tumor growth then goes down."
Developing and testing a new drug to reduce mTORC2 signaling directly could take 10 years or more, but cholesterol-lowering medications are widely available and have been approved by the Food and Drug Administration for heart health, Kim said.
"So you have a safe, widely available intervention that has cardiovascular benefits and could be tested in a large-scale clinical trial to see if it has a beneficial effect on prostate cancer," Kim said. "Our clinical observations in humans and the mechanism of action we identified in animal models make a strong case that this larger clinical trial ought to go forward."
The study was funded by grants from the Samuel Oschin Comprehensive Cancer Institute, Winnick Family Foundation, Homer and Gloria Harvey Family Endowed Chair, the National Institutes of Health under award number R01CA182438, and the National Cancer Institute under award number UG1CA189823 to the Alliance for Clinical Trials in Oncology NCORP Research Base.