title: Tumor immune escape by the loss of homeostatic chemokine expression.
abstract: The novel keratinocyte-specific chemokine CCL27 plays a critical role in the organization of skin-associated immune responses by regulating T cell homing under homeostatic and inflammatory conditions. Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPK-signaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas. In vivo, precancerous skin lesions as well as cutaneous carcinomas showed significantly elevated levels of phosphorylated ERK compared with normal skin, suggesting the activation of EGFR-Ras signaling pathways in keratinocyte-derived malignancies. In vitro, exogenous stimulation of the EGFR-Ras signaling pathway through EGF or transfection of the dominant-active form of the Ras oncogene (H-RasV12) suppressed whereas an EGFR tyrosine kinase inhibitor increased CCL27 mRNA and protein production in keratinocytes. In mice, neutralization of CCL27 led to decreased leukocyte recruitment to cutaneous tumor sites and significantly enhanced primary tumor growth. Collectively, our data identify a mechanism of skin tumors to evade host antitumor immune responses.
authors.affiliation: Department of Dermatology, Heinrich Heine University, D-40255 Düsseldorf, Germany.
authors.forename: Andor
authors.initials: A
authors.lastname: Pivarcsi
authors.forename: Anja
authors.initials: A
authors.lastname: Müller
authors.forename: Andreas
authors.initials: A
authors.lastname: Hippe
authors.forename: Juliane
authors.initials: J
authors.lastname: Rieker
authors.forename: Anke
authors.initials: A
authors.lastname: van Lierop
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
authors.forename: Stephan
authors.initials: S
authors.lastname: Seeliger
authors.forename: Robert
authors.initials: R
authors.lastname: Kubitza
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pippirs
authors.forename: Stephan
authors.initials: S
authors.lastname: Meller
authors.forename: Peter A
authors.initials: PA
authors.lastname: Gerber
authors.forename: Ruediger
authors.initials: R
authors.lastname: Liersch
authors.forename: Erich
authors.initials: E
authors.lastname: Buenemann
authors.forename: Eniko
authors.initials: E
authors.lastname: Sonkoly
authors.forename: Ulrike
authors.initials: U
authors.lastname: Wiesner
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Hoffmann
authors.forename: Leonid
authors.initials: L
authors.lastname: Schneider
authors.forename: Roland
authors.initials: R
authors.lastname: Piekorz
authors.forename: Elaine
authors.initials: E
authors.lastname: Enderlein
authors.forename: Julia
authors.initials: J
authors.lastname: Reifenberger
authors.forename: Ulrich-Peter
authors.initials: UP
authors.lastname: Rohr
authors.forename: Rainer
authors.initials: R
authors.lastname: Haas
authors.forename: Petra
authors.initials: P
authors.lastname: Boukamp
authors.forename: Ingo
authors.initials: I
authors.lastname: Haase
authors.forename: Bernd
authors.initials: B
authors.lastname: Nürnberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruzicka
authors.forename: Albert
authors.initials: A
authors.lastname: Zlotnik
authors.forename: Bernhard
authors.initials: B
authors.lastname: Homey
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology*; D054425:Chemokine CCL27 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010787:Photosensitivity Disorders / Q000276:immunology / Q000378:metabolism; D011230:Precancerous Conditions / Q000276:immunology / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology*; D019139:Tumor Escape / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; C492276:CCL27 protein, human; C119538:Ccl27a protein, mouse; D054425:Chemokine CCL27; D009363:Neoplasm Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras)