Abstract 1344: The ketogenic diet enhances immunity in a mouse model of malignant glioma
Authors: Woolf Eric C. , Johnson John L. , Lussier Danielle M. , Brooks Kenneth S. , Blattman Joseph N. , Scheck Adrienne C. 
Published: August 2015

Abstract
Every year ∼ 14,000 new cases of malignant glioma are diagnosed in the United States. Brain tumors are also the second leading cause of cancer deaths among children and young adults. Indeed, patients with newly diagnosed glioblastoma multiforme (GBM), the most aggressive grade of glioma, have an average life expectancy of 12 to 18 months, and less than 10% survive five years, despite the current standard of care, which consists of aggressive surgery followed by radiation and chemotherapy. Advances in the survival of brain cancer patients require the design of new therapeutic approaches that take advantage of common phenotypes such as the altered metabolism found in cancer cells. It has therefore been postulated that the high-fat, low-carbohydrate, adequate protein ketogenic diet (KD) may be useful in the treatment of brain tumors. We have demonstrated that the KD enhances survival and potentiates standard therapy in a mouse model of malignant glioma. Our mechanistic data suggests that the KD affects multiple aspects of tumor growth including hypoxia, angiogenesis, invasive potential and inflammation. Given the importance of the immune system in the tumor microenvironment and the increased interest in developing anti-cancer immunotherapeutics, the current study sought to explore the KD in the context of infiltration and the functionality of glioma-reactive immune cells.
We used the syngeneic GL261-Luc2 mouse model of malignant glioma and fed mice KetoCal® (KC; 4:1 fat:protein/carbohydrates) ad libitum or a standard rodent diet (SD). Tumor-specific immune cells were isolated from these tumors and tested for functionality via cytokine production, capacity for cytotoxicity, and amount of infiltration. We found that tumor-infiltrating T cells from animals fed KC showed significantly decreased expression of the inhibitory receptors CTLA-4 and PD-1, which coincided with a reduction in expression of the inhibitory ligand on the tumor cells. Moreover, this reduced T cell tolerance at the tumor site allowed CD8+ T cells to produce IFNγ and IL-2, and regain cytotoxic functions. Additionally, the KC caused a reduction in immunosuppressive cytokine production in regulatory T cells. Innate immune responses to the tumor were also altered in mice maintained on KC, as tumor-infiltrating natural killer cells in these animals were able to produce more IFNγ and TNF in response to GL261-luc2 cells in vitro when compared to mice maintained on SD. Overall, the ketogenic diet may be an attractive adjuvant therapy to overcome several immune escape mechanisms in gliomas by decreasing regulatory T cell suppression of effector T cells and increasing CD8+ T cell killing and cytokine production, ultimately leading to increased tumor immune mediated rejection. A greater understanding of the effects of the ketogenic diet as an adjuvant therapy will allow for a more rational approach to its clinical use.
Citation Format: Eric C. Woolf, John L. Johnson, Danielle M. Lussier, Kenneth S. Brooks, Joseph N. Blattman, Adrienne C. Scheck. The ketogenic diet enhances immunity in a mouse model of malignant glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1344. doi:10.1158/1538-7445.AM2015-1344