Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2337-7) contains supplementary material, which is available to authorized users.
Highlights
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 have recently shown that an unrestricted ketogenic diet (KD) decreases expression of the hypoxia marker carbonic anhydrase IX (CAIX) and the key mediator of the hypoxic response hypoxia-inducible factor alpha (HIF-1α) in a mouse model of malignant glioma [9]
In this paper we investigated the role that an unrestricted KD plays in alleviating tumor immune suppression in a mouse model of malignant glioma
Summary
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. Glioblastoma multiforme (GBM) is a highly aggressive, heterogeneous brain tumor with poor prognosis [1]. One novel therapeutic approach for GBM involves targeting a phenotypic trait shared by virtually all cancer cells, deregulated metabolism. The effect of a KD on the GBM tumor-reactive immune response has yet to be examined
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