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Microenvironment and Immunology

Myeloid IKKβ Promotes Antitumor Immunity by Modulating CCL11 and the Innate Immune Response

Jinming Yang, Oriana E. Hawkins, Whitney Barham, Pavlo Gilchuk, Mark Boothby, Gregory D. Ayers, Sebastian Joyce, Michael Karin, Fiona E. Yull and Ann Richmond
Jinming Yang
Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee.Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
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Oriana E. Hawkins
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
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Whitney Barham
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
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Pavlo Gilchuk
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
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Mark Boothby
Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee.Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
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Gregory D. Ayers
Division of Cancer Biostatistics, Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee.
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Sebastian Joyce
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
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Michael Karin
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, California.
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Fiona E. Yull
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
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  • For correspondence: ann.richmond@vanderbilt.eduFiona.Yull@vanderbilt.edu
Ann Richmond
Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee.Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
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  • For correspondence: ann.richmond@vanderbilt.eduFiona.Yull@vanderbilt.edu
DOI: 10.1158/0008-5472.CAN-14-1091
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Abstract

Myeloid cells are capable of promoting or eradicating tumor cells and the nodal functions that contribute to their different roles are still obscure. Here, we show that mice with myeloid-specific genetic loss of the NF-κB pathway regulatory kinase IKKβ exhibit more rapid growth of cutaneous and lung melanoma tumors. In a BRAFV600E/PTEN−/− allograft model, IKKβ loss in macrophages reduced recruitment of myeloid cells into the tumor, lowered expression of MHC class II molecules, and enhanced production of the chemokine CCL11, thereby negatively regulating dendritic-cell maturation. Elevated serum and tissue levels of CCL11 mediated suppression of dendritic-cell differentiation/maturation within the tumor microenvironment, skewing it toward a Th2 immune response and impairing CD8+ T cell–mediated tumor cell lysis. Depleting macrophages or CD8+ T cells in mice with wild-type IKKβ myeloid cells enhanced tumor growth, where the myeloid cell response was used to mediate antitumor immunity against melanoma tumors (with less dependency on a CD8+ T-cell response). In contrast, myeloid cells deficient in IKKβ were compromised in tumor cell lysis, based on their reduced ability to phagocytize and digest tumor cells. Thus, mice with continuous IKKβ signaling in myeloid-lineage cells (IKKβCA) exhibited enhanced antitumor immunity and reduced melanoma outgrowth. Collectively, our results illuminate new mechanisms through which NF-κB signaling in myeloid cells promotes innate tumor surveillance. Cancer Res; 74(24); 1–11. ©2014 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received April 9, 2014.
  • Revision received September 9, 2014.
  • Accepted September 26, 2014.
  • ©2014 American Association for Cancer Research.
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Published OnlineFirst December 5, 2014
doi: 10.1158/0008-5472.CAN-14-1091

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Myeloid IKKβ Promotes Antitumor Immunity by Modulating CCL11 and the Innate Immune Response
Jinming Yang, Oriana E. Hawkins, Whitney Barham, Pavlo Gilchuk, Mark Boothby, Gregory D. Ayers, Sebastian Joyce, Michael Karin, Fiona E. Yull and Ann Richmond
Cancer Res December 5 2014 DOI: 10.1158/0008-5472.CAN-14-1091

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Myeloid IKKβ Promotes Antitumor Immunity by Modulating CCL11 and the Innate Immune Response
Jinming Yang, Oriana E. Hawkins, Whitney Barham, Pavlo Gilchuk, Mark Boothby, Gregory D. Ayers, Sebastian Joyce, Michael Karin, Fiona E. Yull and Ann Richmond
Cancer Res December 5 2014 DOI: 10.1158/0008-5472.CAN-14-1091
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