Myeloid Dendritic Cells from Human Cutaneous Squamous Cell Carcinoma Are Poor Stimulators of T-Cell Proliferation Mark J. Bluth, Lisa C. Zaba, Dariush.

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Myeloid Dendritic Cells from Human Cutaneous Squamous Cell Carcinoma Are Poor Stimulators of T-Cell Proliferation Mark J. Bluth, Lisa C. Zaba, Dariush Moussai, Mayte Suárez-Fariñas, Helen Kaporis, Linda Fan, Katherine C. Pierson, Traci R. White, Alexander Pitts-Kiefer, Judilyn Fuentes-Duculan, Emma Guttman-Yassky, James G. Krueger, Michelle A. Lowes, John A. Carucci Journal of Investigative Dermatology Volume 129, Issue 10, Pages 2451-2462 (October 2009) DOI: 10.1038/jid.2009.96 Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Human cutaneous squamous-cell carcinoma (SCC) is associated with intratumoral CD1a+/Langerin+ Langerhans cells, juxtatumoral CD11c+ myeloid DCs, and BDCA2+ plasmacytoid dendritic cells (DCs). Representative immunohistochemistry (left) and summary data with median cell count values of (a) CD1a, (b) Langerin, (c) CD11c, (d) BDCA-1, and (e) BDCA-2 cells in normal skin, SCC, and juxtatumoral skin. Asterisks (*) indicate significance, where *P<0.05, **P<0.01 and ***P<0.005. Bar=100μm. Journal of Investigative Dermatology 2009 129, 2451-2462DOI: (10.1038/jid.2009.96) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 TNF-α and inducible nitric oxide synthase (iNOS)-producing dendritic cells (TIP-DCs) are found within the squamous-cell carcinoma (SCC) microenvironment. Representative triple-labeled immunofluorescence reveals the presence of CD11c+ myeloid DCs (blue) that also express TNF-α (green) and iNOS (red). Triple positive cells appear white (inset higher fourfold higher magnification). Monochromatic images in upper panel, single pseudocolor controls in middle panel, merged image below. Bar=100μm. Journal of Investigative Dermatology 2009 129, 2451-2462DOI: (10.1038/jid.2009.96) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Phenotypically mature myeloid dendritic cells (DCs) are present in Normal, Peritumoral (PTNL) and squamous-cell carcinoma (SCC)–bearing skin. CD11c+/HLA-DRhi cells from normal skin, peritumoral non-lesion (PTNL), and SCC express maturation markers DC-LAMP, DC-SIGN, DEC-205, and co-stimulatory markers CD83, CD86, and CD80. There were slightly increased DEC-205 and CD86 in myeloid DCs from SCC. Blue lines represent isotype control; mean fluorescence intensity (MFI) value is shown in the upper right hand corner of each histogram (n=3). Journal of Investigative Dermatology 2009 129, 2451-2462DOI: (10.1038/jid.2009.96) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Mature myeloid dendritic cell (DC) gene signature is present in squamous-cell carcinoma (SCC) and peritumoral skin. The mean fold change of published DC gene sets for SCC versus normal skin (black bars) and peritumoral non-lesion (PTNL) versus normal skin (gray bars). Mature DC genes showed increased mean expression in SCC (P<0.004). In PTNL versus normal skin, all gene lists showed increased expression (P<0.05). Data expressed as mean log fold change±standard error. Journal of Investigative Dermatology 2009 129, 2451-2462DOI: (10.1038/jid.2009.96) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Myeloid dendritic cells (DCs) from squamous-cell carcinoma (SCC) are poor stimulators of allogeneic T cells. (a) Representative FACS dot plots of T-cell proliferation with various stimuli, and (b) summary of results with median values indicated. CD3/CD28 beads and monocyte-derived immature DCs (MoDC) stimulate robust T-cell proliferation; unstimulated T cells do not proliferate. Myeloid DCs sorted from normal skin and SCC minimally stimulate T-cell proliferation, and peritumoral non-lesion skin (PTNL) myeloid DCs are slightly more allo-stimulatory. Myeloid DCs from normal skin were most responsive to cytokine cocktail containing IL-1β, IL-6, TNF, and PGE2 (+CYT). Percent live, proliferating T cells indicated in gate. Journal of Investigative Dermatology 2009 129, 2451-2462DOI: (10.1038/jid.2009.96) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 IL-10, TGF-β, and VEGF-A were expressed in the squamous-cell carcinoma (SCC) microenvironment. The relative mRNA expression of (a) IL-10 (b) TGF-β, and (c) VEGF-A relative to HARP in SCC (black bars), peritumoral (PTNL, gray bars) and normal skin (white bars). Data expressed as mean relative mRNA expression±standard error. Asterisks (*) indicate significance, where *P<0.05, **P<0.01 and ***P<0.005. Journal of Investigative Dermatology 2009 129, 2451-2462DOI: (10.1038/jid.2009.96) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions