The addition of a component of the ketogenic diet—a preketone dietary supplement—to immunotherapy showed efficacy in potentially treating prostate cancer in a laboratory setting, according to a recent study published by Murphy et al in Cancer Research.
Background
Although immune checkpoint blockade therapy is designed to block certain proteins from binding with other proteins and enhance T cells’ ability to kill the cancer, prostate cancer is often resistant to this type of therapy.
“Prostate cancer is the most common cancer for men [in the United States], and immunotherapy has been really influential in some other cancers, like melanoma or lung cancer, but it hasn’t been working almost at all for prostate cancer,” stressed senior study author Xin Lu, PhD, the John M. and Mary Jo Boler Collegiate Associate Professor in the Department of Biological Sciences at the University of Notre Dame.
The ketogenic diet is a high-fat, low-carbohydrate diet. Ketones are produced in the body when individuals follow a ketogenic diet.
Study Methods and Results
In the recent study, researchers used mouse models to examine the efficacy of the new approach. They divided the models into six groups: immunotherapy alone, the ketogenic diet alone, the preketone supplement alone, the ketogenic diet plus immunotherapy, the preketone supplement plus immunotherapy, and control.
The researchers found that while immunotherapy alone had almost no effect on the tumors, both the ketogenic diet plus immunotherapy and the preketone supplement plus immunotherapy reduced the cancer and extended the survival of the mouse models. They noted that the preketone supplement plus immunotherapy was most the effective treatment method in the study.
“It turned out this combination worked really well. It made the tumor become very sensitive to the immunotherapy, with 23% of the mice cured—they were tumor-free. [I]n the rest, the tumors were shrinking really dramatically,” Dr. Lu revealed.
The researchers cautioned that any type of dietary study can suffer from the potential issue of causation. Nonetheless, they confirmed their results using single-cell RNA sequencing.
Conclusions
The findings indicated that a supplement providing ketones might prevent the prostate cancer cells from being resistant to immunotherapy and could lead to future clinical studies examining how ketogenic diets or preketone supplements could enhance cancer therapy.
The researchers emphasized that the success of this study was not centered around the lack of carbohydrates. Instead, it was based on the presence of the ketone body, a substance produced by the liver and used as an energy source when glucose is not available. The ketones disrupt the cycle of the cancer cells, allowing the T cells to more effectively destroy cancer cells.
“We found that this combination of the supplement and the immunotherapy reprogrammed the whole immune profile of the tumors and recruited many T cells into the tumors to kill prostate cancer cells,” Dr. Lu underlined. “What’s exciting is that we’re getting closer to the mechanism—backed up by genetic models and what we’re seeing in the tumors themselves—of why this works,” he added.
The therapy also reduced the number of neutrophils present. Once in the tumor microenvironment, neutrophils’ natural properties become greatly distorted. As a result, they can inhibit T-cell activities and allow for tumor progression. Dysregulation of neutrophils is also associated with many other diseases.
“With the main ketone body depleting neutrophils, it opens the door for investigating the effects of the keto diet and the preketone supplement on diseases ranging from inflammatory bowel disease to arthritis,” concluded lead study author Sean Murphy, MS, PhD, of the University of Notre Dame.
Disclosure: The research in this study was supported by the National Institutes of Health, the U.S. Department of Defense, the Boler Family Foundation at the University of Notre Dame, and grants from the American Institute for Cancer Research and the Indiana Clinical and Translational Sciences Institute. For full disclosures of the study authors, visit aacrjournals.org.
