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

(2008) Journal of Experimental Medicine. 205(10). p.2221-2234
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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.
Keywords
SKIN-CANCER, CHRONIC PERIODONTITIS, TOLL-LIKE, NITRIC-OXIDE, IMMUNOMODULATORS IMIQUIMOD, CYTOKINE GENE-EXPRESSION, TRANSCRIPTION FACTOR FOXP3, RECEPTOR-BETA-CHAIN, DENDRITIC CELLS, ADHESION MOLECULE-1

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Citation

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Chicago
Clark, Rachael A, Susan J Huang, George F Murphy, ILSE MOLLET, Dirkjan Hijnen, Manoj Muthukuru, Carl Schanbacher, et al. 2008. “Human Squamous Cell Carcinomas Evade the Immune Response by Down-regulation of Vascular E-selectin and Recruitment of Regulatory T Cells.” Journal of Experimental Medicine 205 (10): 2221–2234.
APA
Clark, R. A., Huang, S. J., Murphy, G. F., MOLLET, I., Hijnen, D., Muthukuru, M., Schanbacher, C., et al. (2008). Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells. Journal of Experimental Medicine, 205(10), 2221–2234.
Vancouver
1.
Clark RA, Huang SJ, Murphy GF, MOLLET I, Hijnen D, Muthukuru M, et al. Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells. Journal of Experimental Medicine. NEW YORK: ROCKEFELLER UNIV PRESS; 2008;205(10):2221–34.
MLA
Clark, Rachael A, Susan J Huang, George F Murphy, et al. “Human Squamous Cell Carcinomas Evade the Immune Response by Down-regulation of Vascular E-selectin and Recruitment of Regulatory T Cells.” Journal of Experimental Medicine 205.10 (2008): 2221–2234. Print.
@article{528123,
  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.},
  author       = {Clark, Rachael A and Huang, Susan J and Murphy, George F and MOLLET, ILSE and Hijnen, Dirkjan and Muthukuru, Manoj and Schanbacher, Carl and Edwards, Vonetta and Miller, Danielle and Kim, Jenny and Lambert, Jo and Kupper, Thomas},
  issn         = {0022-1007},
  journal      = {Journal of Experimental Medicine},
  keywords     = {SKIN-CANCER,CHRONIC PERIODONTITIS,TOLL-LIKE,NITRIC-OXIDE,IMMUNOMODULATORS IMIQUIMOD,CYTOKINE GENE-EXPRESSION,TRANSCRIPTION FACTOR FOXP3,RECEPTOR-BETA-CHAIN,DENDRITIC CELLS,ADHESION MOLECULE-1},
  language     = {eng},
  number       = {10},
  pages        = {2221--2234},
  publisher    = {ROCKEFELLER UNIV PRESS},
  title        = {Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells},
  url          = {http://dx.doi.org/10.1084/JEM.20071190},
  volume       = {205},
  year         = {2008},
}

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