Ketone supplement increases the effectiveness of immunotherapy for prostate cancer

Ketone supplement increases the effectiveness of immunotherapy for prostate cancer

Adding a Pre-Ketone Supplement –; a component of a high-fat, low-carbohydrate ketogenic diet -; Researchers at the University of Notre Dame found that laboratory use of cancer therapy was highly effective in treating prostate cancer.

Recently published online in the magazineCancer research, the study by Xin Lu, an associate professor at the John M. and Mary Jo Boler College in the Department of Biological Sciences, and colleagues addressed a problem that oncologists have struggled with: prostate cancer is resistant to a type of immunotherapy called immune checkpoint blockade (ICB). Therapy. ICB therapy blocks certain proteins from binding to other proteins, paving the way for our body's battle cells, called T cells, to kill the cancer.

"Prostate cancer is the most common cancer in American men, and immunotherapy has had a big impact on some other cancers, such as melanoma or lung cancer, but it has had almost no effect at all on prostate cancer," said Lu, who is affiliated with the Boler-Parseghian Center for Rare and Neglected Diseases. Adding a dietary supplement could overcome this resistance, suggested the study's lead author Sean Murphy.

Murphy, a '24 graduate student who worked as a graduate student in Lu's lab, had been following a keto diet himself. Knowing that cancer cells feed on sugar, he decided to deprive mouse models of carbohydrates. an important part of the keto diet –; could prevent cancer growth.

He divided the models into different groups: immunotherapy alone, ketogenic diet alone, a pre-ketone supplement alone, the ketogenic diet with immunotherapy, the supplement with immunotherapy, and the control. While immunotherapy alone had almost no effect on the tumors (just as it does for most prostate cancer patients), both the ketogenic diet with immunotherapy and preketone supplementation with immunotherapy reduced cancer and extended life in the mouse models.

Supplementing with immunotherapy worked best.

It turned out that this combination worked really well. This made the tumor very sensitive to immunotherapy, 23 percent of the mice were cured -; they were tumor-free; in the rest the tumors shrunk really dramatically.”

Xin Lu, John M. and Mary Jo Boler Collegiate Associate Professor in the Department of Biological Sciences

The evidence raises the possibility that a dietary supplement that provides ketones, which are produced in the body when people eat a keto diet, could prevent prostate cancer cells from becoming resistant to immunotherapy. This may lead to future clinical trials examining how ketogenic diets or keto supplements might improve cancer therapy.

While keto diets allow for a minimal amount of carbohydrates, the success of this study does not depend on the lack of carbohydrates, Murphy and Lu emphasized. This involves the presence of the ketone body, a substance produced by the liver and used as a source of energy when glucose is not available. The ketones disrupt the cycle of the cancer cells and allow the T cells to do their job and destroy them.

The discovery is also exciting at the molecular level, said Lu. Any type of nutritional study can suffer from the potential problem of causality: Are the results of the diet or other changes made due to the diet? However, Lu and his colleagues confirmed their findings using single-cell RNA sequencing, which examines the gene expression of individual cells within the tumor.

“We found that this combination of nutritional supplements and immunotherapy reprogrammed the entire immune profile of the tumors and recruited many T cells into the tumors to kill prostate cancer cells,” Lu said.

The successful therapy also reduced the number of a type of immune cell called neutrophils. Once in the tumor microenvironment, the natural properties of neutrophils are severely distorted and they are largely responsible for inhibiting T cell activities and allowing greater tumor progression. Neutrophil dysregulation is also associated with many other diseases.

"Because the main ketone body depletes neutrophils, this opens the door to studying the effects of the keto diet and ketone supplementation on diseases ranging from inflammatory bowel disease to arthritis," Murphy said.

Lu agreed.

“The exciting thing is that we are getting closer to the mechanism, supported by genetic models and what we see in the tumors themselves, explaining why this works,” he said.

Co-authors include Sharif Rahmy, Dailin Gan, Guoqiang Liu, Yini Zhu, Maxim Manyak, Loan Duong, Jianping He, James H. Schofield, Zachary T. Schafer, Jun Li and Xuemin Lu, all from the University of Notre Dame.

The research was supported by a grant from the American Institute for Cancer Research, funding from the National Institutes of Health, and a core facility grant from the Indiana Clinical and Translational Sciences Institute. Additional support came from the Department of Defense and the Boler Family Foundation at the University of Notre Dame. Based on this study, a provisional patent application was filed by the IDEA Center at Notre Dame.

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