Abstract
Recent findings have shown the significance of CD163-positive macrophages in tumor progression, yet there have been few studies on the function of CD163 in macrophages. Here, we uncover the role of CD163 in macrophage activation using CD163-deficient mice and human samples. We detected CD163 in 62 undifferentiated pleomorphic sarcoma samples, in which a high percentage of CD163-positive macrophages was associated with decreased overall survival and higher histologic grade. We observed macrophage-induced tumor cell proliferation in cocultures of human monocyte-derived macrophages and leiomyosarcoma (TYLMS-1) and myxofibrosarcoma (NMFH-1) cell lines, which was abrogated by silencing of CD163. Tumor development of sarcoma (MCA205 and LM8) cells in CD163-deficient mice was significantly abrogated in comparison with wild-type (WT) mice. Coculture with WT peritoneal macrophages significantly increased proliferation of MCA205 cells but decreased in the presence of CD163-deficient macrophages. Production of IL6 and CXCL2 in CD163-deficient macrophages was suppressed in comparison with WT macrophages, and overexpression of CD163 in CD163-deficient macrophages induced production of IL6 and CXCL2. Silencing of IL6 but not CXCL2 abrogated macrophage-induced proliferation of MCA205 cells. Taken together, our results show that CD163 is involved in protumoral activation of macrophages and subsequent development and progression of tumors in mice and humans.Significance: Macrophage CD163-mediated induction of IL6 promotes tumor development and progression in murine and human malignant tumors. Cancer Res; 78(12); 3255-66. ©2018 AACR.
Highlights
Host-derived immune cells, fibroblasts, and endothelial cells constitute the tumor microenvironment and are known to be related to tumor progression, and macrophages are a critical population of immune cells that induce tumor cell growth, angiogenesis, metastasis, and immune suppression [1,2,3]
CD68 is useful as a pan-macrophage marker; we selected Iba1 instead of CD68 because CD68 positivity was seen in sarcoma cells (Supplementary Fig. S1)
CD163 is a member of the scavenger receptor super family class B and is expressed on myeloid lineages such as monocytes and macrophages [19,20,21]
Summary
Host-derived immune cells, fibroblasts, and endothelial cells constitute the tumor microenvironment and are known to be related to tumor progression, and macrophages are a critical population of immune cells that induce tumor cell growth, angiogenesis, metastasis, and immune suppression [1,2,3]. Macrophages are suggested to be broadly classified into classically activated macrophages (M1/kill macrophages) and alternatively activated macrophages (M2/repair macrophages) according to their functions and expression markers [4,5,6]. Many studies using mouse models have indicated that M1-like macrophages produce proinflammatory cytokines that stimulate antitumor immune. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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