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

R.A. Clark, S.J. Huang, G.F. Murphy, I.G. Mollet, D.J. Hijnen, M. Muthukuru, C.F. Schanbacher, V. Edwards, D.M. Miller, J.E. Kim, J. Lambert, T.S. Kupper

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)2221-2234
Number of pages14
JournalJournal of Experimental Medicine
Issue number10
Publication statusPublished - 29 Sept 2008


  • Aminoquinolines
  • Antigens, CD
  • Antineoplastic Agents
  • Carcinoma, Squamous Cell
  • Cell Movement
  • Down-Regulation
  • E-Selectin
  • Endothelial Cells
  • Forkhead Transcription Factors
  • Humans
  • Immune System
  • Immunologic Memory
  • Interleukin-10
  • Interleukin-6
  • Lymphocyte Activation
  • Nitric Oxide Synthase Type II
  • Skin
  • T-Lymphocyte Subsets
  • T-Lymphocytes, Regulatory
  • Transforming Growth Factor beta
  • Tumor Escape


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