title: Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet.
abstract: Glioblastoma 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.
  
  
  
  The 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.
  
  
  
  We 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.
  
  
  
  The 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.
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, AZ, 85281, USA.|Center for Infectious Diseases and Vaccinology, Biodesign Institute, Arizona State University, Tempe, AZ, 85281, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Lussier
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, AZ, 85281, USA.|Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 W. Thomas Road, Phoenix, AZ, 85013, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Woolf
authors.affiliation: Center for Infectious Diseases and Vaccinology, Biodesign Institute, Arizona State University, Tempe, AZ, 85281, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Johnson
authors.affiliation: Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 W. Thomas Road, Phoenix, AZ, 85013, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Brooks
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, AZ, 85281, USA.|Center for Infectious Diseases and Vaccinology, Biodesign Institute, Arizona State University, Tempe, AZ, 85281, USA.
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Blattman
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, AZ, 85281, USA. Adrienne.scheck@dignityhealth.org.|Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 W. Thomas Road, Phoenix, AZ, 85013, USA. Adrienne.scheck@dignityhealth.org.
authors.forename: Adrienne C
authors.initials: AC
authors.lastname: Scheck
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000178:diet therapy* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D055423:Diet, Ketogenic / Q000379:methods*; D005909:Glioblastoma / Q000178:diet therapy* / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines
keywords: CTLA-4; Glioblastoma; Glioma; Immune inhibitory checkpoints; Immunology; Immunosuppression; Ketogenic diet; Metabolism; Microenvironment; PD-1