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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

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

Authors: Danielle M. Lussier, Eric C. Woolf, John L. Johnson, Kenneth S. Brooks, Joseph N. Blattman, Adrienne C. Scheck

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.
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Literature
1.
Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrent glioblastoma--are we there yet? Neuro Oncol. 2013;15:4–27.CrossRefPubMed
2.
3.
4.
Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 2008;7:500–6.CrossRefPubMed
5.
Stafford P, Abdelwahab MG, Kim DY, Preul MC, Rho JM, Scheck AC. The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutr Metab (Lond). 2010;7:74.CrossRef
6.
Abdelwahab MG, Fenton KE, Preul MC, Rho JM, Lynch A, Stafford P, et al. The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. PLoS One. 2012;7:e36197.CrossRefPubMedPubMedCentral
7.
Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN. The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond). 2007;4:5.CrossRef
8.
Seyfried TN, Flores R, Poff AM, D'Agostino DP, Mukherjee P. Metabolic therapy: a new paradigm for managing malignant brain cancer. Cancer Lett. 2015;356:289–300.CrossRefPubMed
9.
Woolf EC, Curley KL, Liu Q, Turner GH, Charlton JA, Preul MC, et al. The Ketogenic Diet Alters the Hypoxic Response and Affects Expression of Proteins Associated with Angiogenesis, Invasive Potential and Vascular Permeability in a Mouse Glioma Model. PLoS One. 2015;10:e0130357.CrossRefPubMedPubMedCentral
10.
11.
Joon YA, Bazar KA, Lee PY. Tumors may modulate host immunity partly through hypoxia-induced sympathetic bias. Med Hypotheses. 2004;63:352–6.CrossRef
12.
Bruzzese L, Fromonot J, By Y, Durand-Gorde JM, Condo J, Kipson N, et al. NF-kappaB enhances hypoxia-driven T-cell immunosuppression via upregulation of adenosine A(2A) receptors. Cell Signal. 2014;26:1060–7.CrossRefPubMed
13.
Abdelwahab MG, Sankar T, Preul MC, Scheck AC. Intracranial Implantation with Subsequent In Vivo Bioluminescent Imaging of Murine Gliomas. JOVE. 2011;57:e3403.
14.
Jouanneau E, Poujol D, Gulia S, Le MI, Blay JY, Belin MF, et al. Dendritic cells are essential for priming but inefficient for boosting antitumour immune response in an orthotopic murine glioma model. Cancer Immunol Immunother. 2006;55:254–67.CrossRefPubMed
15.
Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, et al. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med. 1998;188:2205–13.CrossRefPubMedPubMedCentral
16.
Villarete L, Somasundaram T, Ahmed R. Tissue-mediated selection of viral variants: correlation between glycoprotein mutation and growth in neuronal cells. J Virol. 1994;68:7490–6.PubMedPubMedCentral
17.
18.
Nduom EK, Weller M, Heimberger AB. Immunosuppressive mechanisms in glioblastoma. Neuro Oncol. 2015;17 Suppl 7:vii9–vii14.CrossRefPubMed
19.
Kmiecik J, Poli A, Brons NH, Waha A, Eide GE, Enger PO, et al. Elevated CD3+ and CD8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level. J Neuroimmunol. 2013;264:71–83.CrossRefPubMed
20.
Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010;11:7–13.CrossRefPubMed
21.
Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, Archer GE, et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res. 2006;66:3294–302.CrossRefPubMed
22.
Husain Z, Huang Y, Seth P, Sukhatme VP. Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells. J Immunol. 2013;191:1486–95.CrossRefPubMed
23.
Wintterle S, Schreiner B, Mitsdoerffer M, Schneider D, Chen L, Meyermann R, et al. Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res. 2003;63:7462–7.PubMed
24.
Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wohrer A, et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro Oncol. 2015;17:1064–75.CrossRefPubMed
25.
Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13:84–8.CrossRefPubMed
26.
Avril T, Saikali S, Vauleon E, Jary A, Hamlat A, De TM, et al. Distinct effects of human glioblastoma immunoregulatory molecules programmed cell death ligand-1 (PDL-1) and indoleamine 2,3-dioxygenase (IDO) on tumour-specific T cell functions. J Neuroimmunol. 2010;225:22–33.CrossRefPubMed
27.
Bloch O, Crane CA, Kaur R, Safaee M, Rutkowski MJ, Parsa AT. Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin Cancer Res. 2013;19:3165–75.CrossRefPubMedPubMedCentral
28.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.CrossRefPubMed
29.
Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27:111–22.CrossRefPubMedPubMedCentral
30.
Fecci PE, Ochiai H, Mitchell DA, Grossi PM, Sweeney AE, Archer GE, et al. Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function. Clin Cancer Res. 2007;13:2158–67.CrossRefPubMed
31.
Vom BJ, Vrohlings M, Haller S, Haimovici A, Kulig P, Sledzinska A, et al. Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection. J Exp Med. 2013;210:2803–11.CrossRef
32.
Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86:343–9.CrossRefPubMedPubMedCentral
33.
Wainwright DA, Chang AL, Dey M, Balyasnikova IV, Kim CK, Tobias A, et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res. 2014;20:5290–301.CrossRefPubMedPubMedCentral
34.
Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, et al. Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model. Cancer Immunol Res. 2016;4:124–35.CrossRefPubMed
35.
36.
37.
Hagemann T, Wilson J, Burke F, Kulbe H, Li NF, Pluddemann A, et al. Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J Immunol. 2006;176:5023–32.CrossRefPubMed
38.
39.
Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75:163–89.CrossRefPubMed
40.
Muller-Hubenthal B, Azemar M, Lorenzen D, Huber M, Freudenberg MA, Galanos C, et al. Tumour Biology: tumour-associated inflammation versus antitumor immunity. Anticancer Res. 2009;29:4795–805.PubMed
41.
42.
Kohrt HE, Nouri N, Nowels K, Johnson D, Holmes S, Lee PP. Profile of immune cells in axillary lymph nodes predicts disease-free survival in breast cancer. PLoS Med. 2005;2:e284.CrossRefPubMedPubMedCentral
43.
Procaccini C, Galgani M, De Rosa V, Matarese G. Intracellular metabolic pathways control immune tolerance. Trends Immunol. 2012;33:1–7.CrossRefPubMed
44.
Rathmell JC, Vander Heiden MG, Harris MH, Frauwirth KA, Thompson CB. In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. Mol Cell. 2000;6:683–92.CrossRefPubMed
45.
46.
Yap M, Brouard S, Pecqueur C, Degauque N. Targeting CD8 T-Cell Metabolism in Transplantation. Front Immunol. 2015;6:547.PubMedPubMedCentral
47.
Lochner M, Berod L, Sparwasser T. Fatty acid metabolism in the regulation of T cell function. Trends Immunol. 2015;36:81–91.CrossRefPubMed
48.
49.
Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill Jr GF. Ketone bodies, potential therapeutic uses. IUBMB Life. 2001;51:241–7.CrossRefPubMed
50.
51.
Sukumar M, Roychoudhuri R, Restifo NP. Nutrient Competition: A New Axis of Tumor Immunosuppression. Cell. 2015;162:1206–8.CrossRefPubMed
Metadata
Title
Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet
Authors
Danielle M. Lussier
Eric C. Woolf
John L. Johnson
Kenneth S. Brooks
Joseph N. Blattman
Adrienne C. Scheck
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2337-7

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