Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells

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 thoug...

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Bibliographic Details
Published in:The Journal of experimental medicine 2008-09, Vol.205 (10), p.2221-2234
Main Authors: Clark, Rachael A, Huang, Susan J, Murphy, George F, Mollet, Ilse G, Hijnen, Dirkjan, Muthukuru, Manoj, Schanbacher, Carl F, Edwards, Vonetta, Miller, Danielle M, Kim, Jenny E, Lambert, Jo, Kupper, Thomas S
Format: Article
Language:English
Subjects:
Aminoquinolines - therapeutic use
Antigens, CD - immunology
Antineoplastic Agents - therapeutic use
Carcinoma, Squamous Cell - drug therapy
Carcinoma, Squamous Cell - immunology
Carcinoma, Squamous Cell - pathology
Cell Movement
Down-Regulation
E-Selectin - genetics
E-Selectin - metabolism
Endothelial Cells - cytology
Endothelial Cells - metabolism
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - metabolism
Humans
Immune System - physiology
Immunologic Memory
Interleukin-10 - immunology
Interleukin-6 - immunology
Lymphocyte Activation
Nitric Oxide Synthase Type II - metabolism
Skin - cytology
Skin - metabolism
Skin - pathology
T-Lymphocyte Subsets - immunology
T-Lymphocytes, Regulatory - immunology
Transforming Growth Factor beta - immunology
Tumor Escape - immunology
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Summary: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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20071190