Keto diet component may increase immunotherapy’s benefit in prostate cancer
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The addition of a pre-ketone supplement to an immunotherapy regimen demonstrated efficacy for treating prostate cancer, according to a study led by researchers at University of Notre Dame.
Prostate cancer’s resistance to immune checkpoint blockade therapy makes use of immunotherapy a challenge.
Previous research suggested a ketogenic diet may enhance response to immune checkpoint blockade; however, adherence to an ongoing ketogenic diet appeared associated with adverse effects.
Xin Lu, PhD, John M. and Mary Jo Boler collegiate associate professor in the department of biological sciences at Notre Dame, and colleagues evaluated several prostate cancer treatment approaches in mouse models: immunotherapy alone, ketogenic diet alone, pre-ketone supplement alone, ketogenic diet plus immunotherapy, pre-ketone supplement with immunotherapy, and controls.
Results showed immunotherapy alone had almost no impact on the tumors; however, the ketogenic diet plus immunotherapy and the pre-ketone supplement plus immunotherapy reduced cancer and improved survival.
“This study highlights the potential of combining metabolic interventions with immunotherapy to overcome resistance and enhance treatment efficacy,” Lu told Healio. “It also underscores the importance of continued research into the interplay between diet, metabolism and immune function in cancer therapy.”
Healio spoke with Lu spoke about the findings and the next steps in research into this treatment strategy.
Healio: Can you explain the rationale for this study?
Lu: This study explores the potential of dietary interventions — specifically a cyclic ketogenic diet regimen and a pre-ketone supplement — to enhance the efficacy of immune checkpoint blockade therapy in prostate cancer. Prostate cancer is notably resistant to immune checkpoint blockade due to its immunosuppressive tumor microenvironment and low immunogenicity. Given the critical need for new treatment strategies for advanced prostate cancer, this study investigates whether metabolic modulation via cyclic ketogenic diet or pre-ketone supplementation can overcome this resistance.
Healio: Why does immunotherapy tend to be less effective for prostate cancer than other malignancies?
Lu: First, prostate cancer typically exhibits a low mutation burden, resulting in fewer neoantigens that the immune system can recognize. Second, the tumor immune microenvironment (TIME) in prostate cancer is highly immunosuppressive, characterized by the presence of regulatory T cells, myeloid-derived suppressor cells and other pro-tumor immune cells. These factors create a challenging environment for effective immune response.
Healio: What prompted you to investigate whether a keto diet can improve outcomes with immunotherapy?
Lu: Previous observations have shown that ketogenic diets can produce the ketone body beta-hydroxybutyrate, which has properties similar to histone deacetylase inhibitors. Histone deacetylase inhibitors are known to enhance the immunogenicity of cancer cells and improve the effectiveness of immune checkpoint blockade therapy. Additionally, a pre-ketone supplement was explored as a potentially more practical and patient-friendly approach to achieve similar therapeutic benefits.
Healio: Can you summarize the findings from your work so far?
Lu: Both a cyclic ketogenic diet and a pre-ketone supplement called 1,3-butanediol, which generates beta-hydroxybutyrate, significantly delayed tumor growth and enhanced the efficacy of immune checkpoint blockade therapy in immune checkpoint blockade-resistant prostate cancer models. The cyclic ketogenic diet and pre-ketone supplementation increased the expression of major histocompatibility class I molecules on cancer cells — making them more detectable to the immune system — and modulated the TIME to favor antitumor immunity. Notably, the pre-ketone supplement combined with immune checkpoint blockade therapy cured 23% of treated mice.
Healio: What might explain the efficacy observed?
Lu: The effectiveness of a cyclic ketogenic diet and pre-ketone supplementation can be attributed to the dual action of beta-hydroxybutyrate (BHB). BHB acts as an endogenous histone deacetylase inhibitor, enhancing the presentation of tumor antigens on cancer cells and making them more recognizable to immune cells. Additionally, BHB modulates the immune system, boosting the activity of cytotoxic T lymphocytes and reprogramming the metabolism of various immune cells to support a more robust antitumor response.
Healio: Do these findings raise new questions?
Lu: Several unanswered questions and challenges remain, including the precise molecular mechanisms through which BHB reprograms immune cell metabolism and function. Further research is needed to determine the optimal dosing and regimen of pre-ketone supplements for humans. Additionally, understanding how these findings translate to other cancer types and investigating potential side effects or resistance mechanisms are crucial next steps.
Healio: What should further research address?
Lu: The next steps in my group involve further preclinical studies to refine the combination therapy and explore its effects on other cancer types. We hope our study will attract interest from the medical community to initiate clinical trials that test the safety and efficacy of the pre-ketone supplement combined with immune checkpoint blockade therapy for patients with advanced prostate cancer. Such trials will help determine the appropriate dosing and provide initial proof of concept for the approach in humans.
Healio: What are the potential implications of this research?
Lu: The long-term goal is to develop a novel therapeutic strategy that can significantly improve the outcomes of immunotherapy for patients with advanced prostate cancer. By making tumors more susceptible to immune attack and enhancing the overall immune response, this approach could increase the effectiveness of existing immunotherapies and provide new treatment options for patients who currently have limited options.
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For more information:
Xin Lu, PhD, can be reached at xlu@nd.edu.
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