Tumor immune escape by the loss of homeostatic chemokine expression.
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.
Pivarcsi
Andor
A
Department of Dermatology, Heinrich Heine University, D-40255 Düsseldorf, Germany.
Müller
Anja
A
Hippe
Andreas
A
Rieker
Juliane
J
van Lierop
Anke
A
Steinhoff
Martin
M
Seeliger
Stephan
S
Kubitza
Robert
R
Pippirs
Ulrich
U
Meller
Stephan
S
Gerber
Peter A
PA
Liersch
Ruediger
R
Buenemann
Erich
E
Sonkoly
Eniko
E
Wiesner
Ulrike
U
Hoffmann
Thomas K
TK
Schneider
Leonid
L
Piekorz
Roland
R
Enderlein
Elaine
E
Reifenberger
Julia
J
Rohr
Ulrich-Peter
UP
Haas
Rainer
R
Boukamp
Petra
P
Haase
Ingo
I
Nürnberg
Bernd
B
Ruzicka
Thomas
T
Zlotnik
Albert
A
Homey
Bernhard
B
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*
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)