Tumor-Associated Macrophages in the Cutaneous SCC Microenvironment Are Heterogeneously Activated Julia S. Pettersen, Judilyn Fuentes-Duculan, Mayte Suárez-Fariñas,

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Tumor-Associated Macrophages in the Cutaneous SCC Microenvironment Are Heterogeneously Activated Julia S. Pettersen, Judilyn Fuentes-Duculan, Mayte Suárez-Fariñas, Katherine C. Pierson, Alexander Pitts-Kiefer, Linda Fan, Daniel A. Belkin, Claire Q.F. Wang, Shivaprasad Bhuvanendran, Leanne M. Johnson-Huang, Mark J. Bluth, James G. Krueger, Michelle A. Lowes, John A. Carucci Journal of Investigative Dermatology Volume 131, Issue 6, Pages 1322-1330 (June 2011) DOI: 10.1038/jid.2011.9 Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Macrophages were more abundant in squamous cell carcinoma (SCC) compared with normal skin. Representative immunohistochemistry (× 10) and cell counts of the macrophage markers (a) CD163 (with an inset of CD163+ cells at × 20) and (b) CD68, showing a significantly increased number of macrophages surrounding SCC tumor nests compared with normal skin. Each dot represents one patient. ***P<0.001. (c) CD163 (green) colocalized with CD68 (red) shown as yellow, but there were CD163+ cells that did not coexpress CD68. (d) CD163 (green) did not coexpress CD11c (red), whereas (e) some CD68+ cells (green) did coexpress CD11c (red) shown as yellow. Bar=100μm. Journal of Investigative Dermatology 2011 131, 1322-1330DOI: (10.1038/jid.2011.9) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Squamous cell carcinoma (SCC) tumor-associated macrophages (TAMs) expressed protumoral products in the tumor microenvironment. Mean mRNA expression of (a) matrix metalloproteinase 9 (MMP9) and (b) MMP11 relative to Human Acidic Ribosomal Protein (HARP) after adjustment for batch effect in normal skin (white bars), nontumoral skin (NT, gray bars), and SCC (black bars) with SEM. *P<0.05, **P<0.01. CD163+ cells (green) demonstrated abundant colocalization with (c) MMP9 (red) and (d) MMP11 (red) in SCC compared with normal skin. Double-positive cells appear yellow. Bar=100μm. Journal of Investigative Dermatology 2011 131, 1322-1330DOI: (10.1038/jid.2011.9) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Squamous cell carcinoma (SCC) tumor-associated macrophages (TAMs) expressed products of alternatively activated macrophages. Many CD163+ cells (green) coexpressed (a) phosphorylated signal transducer and activator of transcription 6 (STAT6p; red), (b) CD209/DC-SIGN (red), and (c) chemokine (C-C motif) ligand 18 (CCL18; red) compared with normal skin. Double-positive cells appear yellow. Bar=100μm. Journal of Investigative Dermatology 2011 131, 1322-1330DOI: (10.1038/jid.2011.9) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 SCC tumor-associated macrophages (TAMs) expressed characteristics of classically activated macrophages in a microenvironment with type 1 activation. Compared with normal skin, CD163+ cells coexpressed (a) phosphorylated signal transducer and activator of transcription 1 (STAT1p; red), (b) CD127/IL7R (red), (c) IL-23p19 (red), and (d) IL-12/IL-23p40 (green). Double-positive cells appear yellow. Bar=100μm. Journal of Investigative Dermatology 2011 131, 1322-1330DOI: (10.1038/jid.2011.9) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 A subset of SCC tumor-associated macrophages (TAMs) simultaneously expressed characteristics of both classical and alternative activation. Triple-labeled confocal immunofluorescence revealed the presence of (a) CD163+ cells (blue) that simultaneously coexpressed phosphorylated signal transducer and activator of transcription 6 (STAT6p; green) and STAT1p (red) and (b) CD163+ cells (green) that simultaneously coexpressed the markers CD127 (red) and CD209 (blue) in SCC. Triple-positive cells (white) are indicated by arrows. Bar=100μm. (c) The proposed model of SCC macrophage polarization. Th1 and Th2 cells produce cytokines, IFN-γ and IL-4, respectively, and act on resident CD163+ macrophages to polarize these cells in several directions. IFN-γ stimulates the M1 phenotype (CD127 and IL-23), and IL-4 stimulates toward the M2 phenotype (CD209 and chemokine (C-C motif) ligand 18 (CCL18)). There is also production of mediators that are not driven by known polarizing cytokines, such as matrix metalloproteinase 9 (MMP9), MMP11, and vascular endothelial growth factor-C (VEGF-C). The overall outcome is a poly-activated TAM. Journal of Investigative Dermatology 2011 131, 1322-1330DOI: (10.1038/jid.2011.9) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions