Fiona Yull

Last active: 3/21/2018

Myeloid IKKβ promotes antitumor immunity by modulating CCL11 and the innate immune response.

Yang J, Hawkins OE, Barham W, Gilchuk P, Boothby M, Ayers GD, Joyce S, Karin M, Yull FE, Richmond A
Cancer Res. 2014 74 (24): 7274-84

PMID: 25336190 · PMCID: PMC4349570 · DOI:10.1158/0008-5472.CAN-14-1091

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.

©2014 American Association for Cancer Research.

MeSH Terms (15)

Animals CD8-Positive T-Lymphocytes Dendritic Cells Humans I-kappa B Kinase Immunity, Innate Macrophages Melanoma, Experimental Mice Mice, Knockout Myeloid Cells NF-kappa B Proto-Oncogene Proteins B-raf Signal Transduction Tumor Microenvironment

Connections (7)

This publication is referenced by other Labnodes entities:

Links