Tumor immune escape by the loss of homeostatic chemokine expression

被引:105
作者
Pivarcsi, Anclor
Mueller, Ania
Hippe, Andreas
Rieker, Juliane
van Lierop, Anke
Steinhoff, Martin
Seeliger, Stephan
Kubitza, Robert
Pippirs, Ulrich
Meller, Stephan
Gerber, Peter A.
Liersch, Ruediger
Buenemann, Erich
Sonkoly, Eniko
Wiesner, Ulrike
Hoffmann, Thomas K.
Schneider, Leonid
Piekorz, Roland
Enderlein, Elaine
Reifenberger, Julia
Rohr, Ulrich-Peter
Haas, Rainer
Boukamp, Petra
Haase, Ingo
Nuernberg, Bernd
Ruzicka, Thomas
Zlotnik, Albert
Homey, Bernhard
机构
[1] Univ Dusseldorf, Dept Dermatol, D-40255 Dusseldorf, Germany
[2] Univ Dusseldorf, Dept Radiat Oncol, D-40255 Dusseldorf, Germany
[3] Univ Dusseldorf, Dept Otorhinolaryngol, D-40255 Dusseldorf, Germany
[4] Univ Dusseldorf, Dept Biochem & Mol Biol 2, D-40255 Dusseldorf, Germany
[5] Univ Dusseldorf, Dept Hematol Oncol & Clin Immunol, D-40255 Dusseldorf, Germany
[6] Univ Munster, Dept Dermatol, D-48149 Munster, Germany
[7] Univ Munster, Dept Hematooncol, D-48149 Munster, Germany
[8] Univ Munster, Dept Pediat, D-48149 Munster, Germany
[9] German Canc Res Ctr, Dept Genet Skin Carcinogenesis, D-69120 Heidelberg, Germany
[10] Univ Cologne, Dept Dermatol, D-50923 Cologne, Germany
[11] Univ Munich, Dept Dermatol, D-80336 Munich, Germany
[12] Neurocrine Biosci Inc, San Diego, CA 92121 USA
关键词
cancer; CCL27/CTACK; skin; immune surveillance; EGDR/R pathway;
D O I
10.1073/pnas.0705673104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:19055 / 19060
页数:6
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