Clark RA, Huang SJ, Murphy GF et al.Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells. J Exp Med 205:2221-2234

Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 10/2008; 205(10):2221-34. DOI: 10.1084/jem.20071190
Source: PubMed

ABSTRACT Squamous cell carcinomas (SCCs) of the skin are sun-induced skin cancers that are particularly numerous in patients on T cell immunosuppression. We found that blood vessels in SCCs did not express E-selectin, and tumors contained few cutaneous lymphocyte antigen (CLA)(+) T cells, the cell type thought to provide cutaneous immunosurveillance. Tumors treated with the Toll-like receptor (TLR)7 agonist imiquimod before excision showed induction of E-selectin on tumor vessels, recruitment of CLA(+) CD8(+) T cells, and histological evidence of tumor regression. SCCs treated in vitro with imiquimod also expressed vascular E-selectin. Approximately 50% of the T cells infiltrating untreated SCCs were FOXP3(+) regulatory T (T reg) cells. Imiquimod-treated tumors contained a decreased percentage of T reg cells, and these cells produced less FOXP3, interleukin (IL)-10, and transforming growth factor (TGF)-beta. Treatment of T reg cells in vitro with imiquimod inhibited their suppressive activity and reduced FOXP3, CD39, CD73, IL-10, and TGF-beta by indirect mechanisms. In vivo and in vitro treatment with imiquimod also induced IL-6 production by effector T cells. In summary, we find that SCCs evade the immune response at least in part by down-regulating vascular E-selectin and recruiting T reg cells. TLR7 agonists neutralized both of these strategies, supporting their use in SCCs and other tumors with similar immune defects.

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    • "Importantly, studies in a variety of cancers suggest that improved T cell infiltration and function may be achieved by therapeutic modulation of pathways regulating E-selectin (Clark et al, 2008) and protein nitration (Molon et al, 2011). Specifically, E-selectin induction has been observed in vitro with TNF-α and IL-1 cytokines (Wyble et al, 1997), angiostatins (Luo et al, 1998) and topical imiquimod (Clark et al, 2008). "
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    ABSTRACT: Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-linked skin cancer. While CD8 lymphocyte infiltration into the tumor is strongly correlated with improved survival, these cells are absent or sparse in most MCCs. We investigated whether specific mechanisms of T-cell migration may be commonly disrupted in MCC tumors with poor CD8 lymphocyte infiltration. Intratumoral vascular E-selectin, critical for T-cell entry into skin, was downregulated in the majority (52%) of MCCs (n=56), and its loss was associated with poor intratumoral CD8 lymphocyte infiltration (P<0.05; n=45). Importantly, survival was improved in MCC patients whose tumors had higher vascular E-selectin expression (P<0.05). Local nitric oxide (NO) production is one mechanism of E-selectin downregulation and it can be tracked by quantifying nitrotyrosine, a stable biomarker of NO-induced reactive nitrogen species (RNS). Indeed, increasing levels of nitrotyrosine within MCC tumors were associated with low E-selectin expression (P<0.05; n=45) and decreased CD8 lymphocyte infiltration (P<0.05, n=45). These data suggest that one mechanism of immune evasion in MCC may be restriction of T cell entry into the tumor. Existing therapeutic agents that modulate E-selectin expression and/or RNS generation may restore T cell entry and could potentially synergize with other immune-stimulating therapies.Journal of Investigative Dermatology accepted article preview online, 25 January 2013;doi:10.1038/jid.2013.36.
    Journal of Investigative Dermatology 01/2013; 133(8). DOI:10.1038/jid.2013.36 · 6.37 Impact Factor
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    • "The induction of this T cell subtype by activin A has also been confirmed in a mouse model of allergic airway disease (Semitekolou et al., 2009). An important role of Tregs in the pathogenesis of human skin cancer appears probable, as they have been shown to infiltrate human squamous cell carcinomas and to be at least partly responsible for the evasion of the host immune response by these tumours (Clark et al., 2008). "
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    ABSTRACT: Activin was initially described as a protein that stimulates release of follicle stimulating hormone from the pituitary, and it is well known for its important roles in different reproductive functions. In recent years, this multifunctional factor has attracted the attention of researchers in other fields, as new functions of activin in angiogenesis, inflammation, immunity, fibrosis and cancer have been discovered. Studies from our laboratory have identified activin as a crucial regulator of wound healing and skin carcinogenesis. On the one hand, it strongly accelerates the healing process of skin wounds but, on the other hand, it enhances scar formation and the susceptibility to skin tumorigenesis. Finally, results from several laboratories have revealed that activin enhances tumour formation and/or progression in some other organs, in particular through its effect on the tumour microenvironment, and that it also promotes cancer-induced bone disruption and muscle wasting. These findings provide the basis for the use of activin or its downstream targets for the improvement of impaired wound healing, and of activin antagonists for the prevention and treatment of fibrosis and of malignant tumours that overexpress activin. Here, we summarize the previously described roles of activin in wound healing and scar formation and discuss functional studies that revealed different functions of activin in the pathogenesis of cancer. The relevance of these findings for clinical applications will be highlighted.
    Journal of Cell Science 09/2012; 125(17). DOI:10.1242/jcs.094789 · 5.33 Impact Factor
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    • "de the population of CLA + T cells thought to provide immune surveillance in the skin ( Clark et al . , 2008 ) . Induction of E - selectin expression on blood vessels by TLR7 agonist therapy leads to infiltration of the tumors by CLA + T cells producing IFNγ , perforin and granzyme , and is associated with histologic evidence of tumor regression ( Clark et al . , 2008 ; Huang et al . , 2009 ) . These clinical responses suggest that tumor specific T cells exist within the circulation but cannot gain access to the tumor . Thus , the induction of appropriate T cell homing addressins on tumor vessels has the potential to restore homing and potentially induce tumor destruction ."
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    ABSTRACT: Squamous cell carcinomas (SCCs) are sun-induced skin cancers that are particularly numerous and aggressive in immunosuppressed individuals. SCCs evade immune detection at least in part by downregulating E-selectin on tumor vessels, thereby restricting entry of skin-homing T cells into tumors. We find that nitric oxide (NO) potently suppresses E-selectin expression on human endothelial cells and that SCCs are infiltrated by NO-producing iNOS(+) CD11b(+) CD33(+) CD11c(-) HLA-DR(-) myeloid-derived suppressor cells (MDSCs). MDSCs from SCCs produced NO, transforming growth factor-β (TGF-β), and arginase, and inhibited endothelial E-selectin expression in vitro. MDSCs from SCCs expressed the chemokine receptor CCR2 (chemokine (C-C motif) receptor 2) and tumors expressed the CCR2 ligand human β-defensin 3 (HBD3), suggesting that CCR2/HBD3 interactions may contribute to MDSC recruitment to SCCs. Treatment of SCCs in vitro with the inducible nitric oxide synthase (iNOS) inhibitor N(ω)-nitro-L-arginine(L-NNA) induced E-selectin expression at levels comparable to imiquimod-treated SCCs undergoing immunologic destruction. Our results suggest that local production of NO in SCCs may impair vascular E-selectin expression. We show that MDSCs are critical producers of NO in SCCs and that NO inhibition restores vascular E-selectin expression, potentially enhancing T-cell recruitment. The iNOS inhibitors and other therapies that reduce NO production may therefore be effective in the treatment of SCCs and their premalignant precursor lesions, actinic keratoses.
    Journal of Investigative Dermatology 06/2012; 132(11):2642-51. DOI:10.1038/jid.2012.190 · 6.37 Impact Factor
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