Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet

BMC Cancer

Research Article

John L. Johnson¹  Kenneth S. Brooks²  Danielle M. Lussier³  Joseph N. Blattman³  Eric C. Woolf⁴  Adrienne C. Scheck⁴ 

[1] Center for Infectious Diseases and Vaccinology, Biodesign Institute, Arizona State University, 85281, Tempe, AZ, USA;Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, 350 W. Thomas Road, 85013, Phoenix, AZ, USA;School of Life Sciences, Arizona State University, 85281, Tempe, AZ, USA;Center for Infectious Diseases and Vaccinology, Biodesign Institute, Arizona State University, 85281, Tempe, AZ, USA;School of Life Sciences, Arizona State University, 85281, Tempe, AZ, USA;Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, 350 W. Thomas Road, 85013, Phoenix, AZ, USA;

关键词: Glioblastoma;    Glioma;    Ketogenic diet;    Metabolism;    Immunosuppression;    Microenvironment;    Immune inhibitory checkpoints;    Immunology;    CTLA-4;    PD-1;   

DOI  :  10.1186/s12885-016-2337-7

 received in 2016-01-05, accepted in 2016-05-04,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundGlioblastoma multiforme is a highly aggressive brain tumor with a poor prognosis, and advances in treatment have led to only marginal increases in overall survival. We and others have shown previously that the therapeutic ketogenic diet (KD) prolongs survival in mouse models of glioma, explained by both direct tumor growth inhibition and suppression of pro-inflammatory microenvironment conditions. The aim of this study is to assess the effects of the KD on the glioma reactive immune response.MethodsThe GL261-Luc2 intracranial mouse model of glioma was used to investigate the effects of the KD on the tumor-specific immune response. Tumor-infiltrating CD8+ T cells, CD4+ T cells and natural killer (NK) cells were analyzed by flow cytometry. The expression of immune inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) on CD8+ T cells were also analyzed by flow cytometry. Analysis of intracellular cytokine production was used to determine production of IFN, IL-2 and IFN- in tumor-infiltrating CD8+ T and natural killer (NK) cells and IL-10 production by T regulatory cells.ResultsWe demonstrate that mice fed the KD had increased tumor-reactive innate and adaptive immune responses, including increased cytokine production and cytolysis via tumor-reactive CD8+ T cells. Additionally, we saw that mice maintained on the KD had increased CD4 infiltration, while T regulatory cell numbers stayed consistent. Lastly, mice fed the KD had a significant reduction in immune inhibitory receptor expression as well as decreased inhibitory ligand expression on glioma cells.ConclusionsThe KD may work in part as an immune adjuvant, boosting tumor-reactive immune responses in the microenvironment by alleviating immune suppression. This evidence suggests that the KD increases tumor-reactive immune responses, and may have implications in combinational treatment approaches.

【 授权许可】

CC BY   
© Lussier et al. 2016