Intermittent fasting induced ketogenesis inhibits mouse epithelial ovarian cancer by promoting antitumor T cell response
Mary Priyanka Udumula,
Harshit Singh,
Faraz Rashid,
Laila Poisson,
Nivedita Tiwari,
Irina Dimitrova,
Miriana Hijaz,
Radhika Gogoi,
Margaret Swenor,
Adnan Munkarah,
Shailendra Giri,
Ramandeep Rattan
Affiliations
Mary Priyanka Udumula
Department of Women’s Health Services, Henry Ford Hospital and Henry Ford Cancer Institute, Detroit, MI, USA
Harshit Singh
Department of Women’s Health Services, Henry Ford Hospital and Henry Ford Cancer Institute, Detroit, MI, USA
Faraz Rashid
Metabolomics Core, Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA
Laila Poisson
Department of Public Health Services and Center for Bioinformatics and Henry Ford Cancer Institute, Detroit, MI, USA
Nivedita Tiwari
Department of Women’s Health Services, Henry Ford Hospital and Henry Ford Cancer Institute, Detroit, MI, USA
Irina Dimitrova
Department of Women’s Health Services, Henry Ford Hospital and Henry Ford Cancer Institute, Detroit, MI, USA
Miriana Hijaz
Department of Women’s Health Services, Henry Ford Hospital and Henry Ford Cancer Institute, Detroit, MI, USA
Radhika Gogoi
Department of Gynecology Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA
Margaret Swenor
Department of Lifestyle and Functional Medicine, Henry Ford Hospital and Henry Ford Cancer Institute, Detroit, MI, USA
Adnan Munkarah
Department of Women’s Health Services, Henry Ford Hospital and Henry Ford Cancer Institute, Detroit, MI, USA
Shailendra Giri
Metabolomics Core, Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA
Ramandeep Rattan
Department of Women’s Health Services, Henry Ford Hospital and Henry Ford Cancer Institute, Detroit, MI, USA; Department of Oncology, Wayne State University, Detroit, MI, USA; Department of Ob/Gyn, Michigan State University, East Lansing, MI, USA; Corresponding author
Summary: In various cancer models, dietary interventions have been shown to inhibit tumor growth, improve anticancer drug efficacy, and enhance immunity, but no such evidence exists for epithelial ovarian cancer (EOC), the most lethal gynecologic cancer. The anticancer immune responses induced by 16-h intermittent fasting (IF) were studied in mice with EOC. IF consistently reduced metabolic growth factors and cytokines that stimulate tumor growth, creating a tumor-hostile environment. Immune profiling showed that IF dramatically alters anti-cancer immunity by increasing CD4+ and CD8+ cells, Th1 and cytotoxic responses, and metabolic fitness. β-hydroxy butyrate (BHB), a bioactive metabolite produced by IF, partially imitates its anticancer effects by inducing CD8+ effector function. In a direct comparison, IF outperformed exogenous BHB treatment in survival and anti-tumor immune response, probably due to increased ketogenesis. Thus, IF and one of its metabolic mediators BHB suppress EOC growth and sustain a potent anti-tumor T cell response.
