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Beta-glucan-induced inflammatory monocytes mediate antitumor efficacy in the murine lung

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Abstract

β-Glucan is a naturally occurring glucose polysaccharide with immunostimulatory activity in both infection and malignancy. β-Glucan’s antitumor effects have been attributed to the enhancement of complement receptor 3-dependent cellular cytotoxicity, as well as modulation of suppressive and stimulatory myeloid subsets, which in turn enhances antitumor T cell immunity. In the present study, we demonstrate antitumor efficacy of yeast-derived β-glucan particles (YGP) in a model of metastatic-like melanoma in the lung, through a mechanism that is independent of previously reported β-glucan-mediated antitumor pathways. Notably, efficacy is independent of adaptive immunity, but requires inflammatory monocytes. YGP-activated monocytes mediated direct cytotoxicity against tumor cells in vitro, and systemic YGP treatment upregulated inflammatory mediators, including TNFα, M-CSF, and CCL2, in the lungs. Collectively, these studies identify a novel role for inflammatory monocytes in β-glucan-mediated antitumor efficacy, and expand the understanding of how this immunomodulator can be used to generate beneficial immune responses against metastatic disease.

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Abbreviations

β-Glucan:

β-1,3 Backbone of d-glucose with β-1,6 branches of variable length and complexity

CR3:

Complement receptor 3

DT:

Diphtheria toxin

iC3b:

Inactivated complement component 3b

Mφ:

Macrophages

Mo:

Monocytes

mHIF1α−/− :

Myeloid-specific knockout of HIF1α

TII:

Trained innate immunity

YGP:

Yeast-derived β-glucan particles

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Acknowledgements

We thank Brent L. Berwin, Constance E. Brinkerhoff, Marc S. Ernstoff, John Frelinger, and Irene M. Mullins for helpful suggestions and feedback. We thank Jennifer L. Vella and Yina H. Huang for assistance with B16.F10-luciferase cells.

Funding

Matthew P. Alexander was supported, in part, through the Joanna M. Nicolay Melanoma Foundation. David W. Mullins was supported, in part, through USPHS R03 CA188418. Flow cytometry and multiplex assays were carried out in DartLab, the Immune Monitoring and Flow Cytometry Shared Resource, supported by a National Cancer Institute Cancer Center Support Grant to the Norris Cotton Cancer Center (P30CA023108-37) and an Immunology COBRE Grant (P30GM103415-15) from the National Institute of General Medical Sciences.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA

    Matthew P. Alexander, Steven N. Fiering, Robert A. Cramer & David W. Mullins

  2. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA

    Matthew P. Alexander, Steven N. Fiering & David W. Mullins

  3. Department of Medical Education, Geisel School of Medicine at Dartmouth, 45 Dewey Field Road, HB7100, Hanover, NH, 03755, USA

    David W. Mullins

  4. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA

    Gary R. Ostroff

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  1. Matthew P. Alexander
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Contributions

MPA performed all in vitro and mouse model studies, participated in data and statistical analyses, and contributed to the drafting of the manuscript. SNF contributed to study design and data analysis, and participated in drafting of the manuscript. GRO generated YGP β-glucan, contributed to study design and data analysis, and participated in drafting of the manuscript. RAC maintained and provided Myeloid-HIF1α−/− mice, contributed to study design and data analysis, and participated in drafting of the manuscript. DWM participated in in vitro and mouse model studies, oversaw study design and data/statistical analyses, and contributed to the drafting of the manuscript.

Corresponding author

Correspondence to David W. Mullins.

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Conflict of interest

David W. Mullins is a senior scientific advisor and has received research grants, unrelated to the current work, from Qu Biologics (Vancouver, BC). The remaining authors declare no conflict of interest.

Animal studies

C57BL/6J (stock no. 000664) and CCR2−/− mice (stock no. 004999) mice were obtained from Jackson Laboratories (Bar Harbor, ME). CCR2.DTR mice were a gift from Dr. Tobias Hohl (Memorial Sloan Kettering Cancer Center). Myeloid-HIF1α−/− mice (LysM-Cre floxed-HIF1α exon 2) were generated and bred in house at Dartmouth by Dr. Robert A. Cramer.

Ethical approval

All animal care procedures and experimental protocols were performed in accordance with all applicable international, national, and/or institutional guidelines for the care and use of animals. All animal care procedures and experimental protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of Dartmouth College (protocol 1141).

Cell line authentication

B16-F10 were newly acquired from ATCC, then expanded and cryopreserved to create individual aliquots that were used for each study. B16.F10-luciferase cells were generated from new aliqouts of B16-F10. Cells were confirmed to be free of Mycoplasma infection using the Hek Blue Mycoplasma Detection Kit from Invivogen.

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Alexander, M.P., Fiering, S.N., Ostroff, G.R. et al. Beta-glucan-induced inflammatory monocytes mediate antitumor efficacy in the murine lung. Cancer Immunol Immunother 67, 1731–1742 (2018). https://doi.org/10.1007/s00262-018-2234-9

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