Journal Article

Tumor immune escape by the loss of homeostatic chemokine expression

Haas, Rainer, Müller, Anja, Schneider, Leonid, Haase, Ingo, Meller, Stephan, Wiesner, Ulrike, Sonkoly, Eniko, Rohr, Ulrich-Peter, Buenemann, Erich, Hippe, Andreas, Homey, Bernhard, Hoffmann, Thomas K, Kubitza, Robert, Reifenberger, Julia, Liersch, Ruediger, Enderlein, Elaine, Pivarcsi, Andor, Rieker, Juliane, Gerber, Peter A, Steinhoff, Martin, Piekorz, Roland, Seeliger, Stephan, Pippirs, Ulrich, Zlotnik, Albert, Ruzicka, Thomas, van Lierop, Anke, Boukamp, Petra, Nürnberg, Bernd

2007

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / Antibodies / Antibodies, Monoclonal - pharmacology / Antibodies, Monoclonal - therapeutic use / Biological Sciences / carcinoma / Carcinoma, Basal Cell - genetics / Carcinoma, Basal Cell - immunology / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - immunology / Cells / chemokine CCL27 / Chemokine CCL27 - antagonists & inhibitors / Chemokine CCL27 - biosynthesis / Chemokine CCL27 - genetics / Chemokine CCL27 - physiology / Chemokines / Cytotoxicity, Immunologic / Down-Regulation / epidermal growth factor receptors / Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors / Extracellular Signal-Regulated MAP Kinases - metabolism / Gene expression / Gene Expression Regulation, Neoplastic / Humans / immune response / Immune system / Keratinocytes / Keratinocytes - metabolism / Lymph nodes / Melanoma, Experimental - genetics / Melanoma, Experimental - immunology / Melanoma, Experimental - metabolism / Messenger RNA / Mice / Mice, Inbred C57BL / mitogen-activated protein kinase / Neoplasm Proteins - biosynthesis / Neoplasm Proteins - genetics / Neoplasm Proteins - physiology / Neutralization / oncogenes / Photosensitivity Disorders - immunology / Photosensitivity Disorders - metabolism / Precancerous Conditions - immunology / Precancerous Conditions - metabolism / protein synthesis / Proto-Oncogene Proteins p21(ras) - physiology / Receptor, Epidermal Growth Factor - antagonists & inhibitors / Receptor, Epidermal Growth Factor - physiology / Signal Transduction / Skin / Skin cancers / skin lesions / skin neoplasms / Skin Neoplasms - genetics / Skin Neoplasms - immunology / T lymphocytes / transfection / Tumor Escape - physiology / Tumors / tyrosine