title: Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells.
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.
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA. rclark1@partners.org
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Clark
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Huang
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.forename: Ilse G
authors.initials: IG
authors.lastname: Mollet
authors.forename: Dirkjan
authors.initials: D
authors.lastname: Hijnen
authors.forename: Manoj
authors.initials: M
authors.lastname: Muthukuru
authors.forename: Carl F
authors.initials: CF
authors.lastname: Schanbacher
authors.forename: Vonetta
authors.initials: V
authors.lastname: Edwards
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Miller
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Kim
authors.forename: Jo
authors.initials: J
authors.lastname: Lambert
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kupper
mesh_terms: D000634:Aminoquinolines / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement; D015536:Down-Regulation; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000077271:Imiquimod; D007107:Immune System / Q000502:physiology; D007156:Immunologic Memory; D016753:Interleukin-10 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008213:Lymphocyte Activation; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D000634:Aminoquinolines; D015703:Antigens, CD; D000970:Antineoplastic Agents; D019040:E-Selectin; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D052247:Nitric Oxide Synthase Type II; D000077271:Imiquimod
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