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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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    • "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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    • "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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