title: Myeloid IKKβ promotes antitumor immunity by modulating CCL11 and the innate immune response.
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 BRAF(V600E/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 (IKKβ(CA)) 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.
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Jinming
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Oriana E
authors.initials: OE
authors.lastname: Hawkins
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Whitney
authors.initials: W
authors.lastname: Barham
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Pavlo
authors.initials: P
authors.lastname: Gilchuk
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee. Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Mark
authors.initials: M
authors.lastname: Boothby
authors.affiliation: Division of Cancer Biostatistics, Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Ayers
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Joyce
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. ann.richmond@vanderbilt.edu Fiona.Yull@vanderbilt.edu.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Yull
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. ann.richmond@vanderbilt.edu Fiona.Yull@vanderbilt.edu.
authors.forename: Ann
authors.initials: A
authors.lastname: Richmond
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003713:Dendritic Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics* / Q000378:metabolism; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology; D008546:Melanoma, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*
chemical_list: D016328:NF-kappa B; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D051550:I-kappa B Kinase