Deutsche Übersetzung des Titels: Toleranz von Dendritische Zellen in ret transgeische Mausmodel

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Abstract

To investigate mechanisms of the dendritic cell (DC) dysfunction during tumor progression, a transgenic murine model of spontaneous melanoma was used. Ret transgenic mice overexpress the human proto-oncogene ret in melanin containing cells and develop skin malignant melanoma which closely resembles human melanoma with respect to tumor genetics, histopathology and clinical development. Numbers of total DCs (MHCII+ CD11c+ cells) and mature DCs (DCs expressing CD40, CD80, or CD86) were found to be significantly decreased in the spleen, lymph nodes and bone marrow of tumor bearing mice as compared to ret transgenic tumor free or wild type mice (control groups). Moreover, tumors recruited more DCs during progression but the tumor infiltrating DCs were blocked at the immature stage. After stimulation in vitro, ex vivo isolated DCs or those generated from bone marrow precursors from tumor bearing mice produced significantly more IL-10 and less IL-12 than DCs from control mice, showing a tolerogenic cytokine pattern. DCs from tumor bearing mice displayed also significantly less capacity to stimulate CD8+ T cells to produce IFN-. Therefore, the phenotype and function of DCs in ret transgenic mice showed the characteristics of tolerogenic DCs. Melanoma-derived factors in ret transgenic mice were demonstrated to be involved in the acquisition of tolerogenic properties, since DCs generated from bone marrow precursors in medium supplemented with mouse melanoma cell conditioned medium produced significantly less IL-12. Moreover, when activity of VEGF, IL-6, or TGF- was blocked with the respective neutralizing antibodies, IL-12 production by DCs was significantly upregulated. The p38 mitogen-activated protein kinase (MAPK) can be activated by different tumor-derived factors. A considerably elevated expression of the phosphorylated form of p38 MAPK was detected in DCs from tumor bearing mice. Suppression of p38 MAPK activity in DCs from tumor bearing mice in vitro was found to lead to normalization of their cytokine expression pattern and T-cell stimulation capacity. Taken together, constitutive activation of p38 MAPK is responsible for turning of DCs to display a tolerogenic profile in the process of melanoma development. We have demonstrated that suppression of the p38 MAPK activity in DCs from ret tumor bearing mice can reconstitute their impaired cytokine secretion pattern and ability to stimulate T cells suggesting thereby that such normalization of signaling pathways in DCs could represent an effective immunotherapeutic strategy in melanoma patients.

Übersetzung des Abstracts (Englisch)

To investigate mechanisms of the dendritic cell (DC) dysfunction during tumor progression, a transgenic murine model of spontaneous melanoma was used. Ret transgenic mice overexpress the human proto-oncogene ret in melanin containing cells and develop skin malignant melanoma which closely resembles human melanoma with respect to tumor genetics, histopathology and clinical development. Numbers of total DCs (MHCII+ CD11c+ cells) and mature DCs (DCs expressing CD40, CD80, or CD86) were found to be significantly decreased in the spleen, lymph nodes and bone marrow of tumor bearing mice as compared to ret transgenic tumor free or wild type mice (control groups). Moreover, tumors recruited more DCs during progression but the tumor infiltrating DCs were blocked at the immature stage. After stimulation in vitro, ex vivo isolated DCs or those generated from bone marrow precursors from tumor bearing mice produced significantly more IL-10 and less IL-12 than DCs from control mice, showing a tolerogenic cytokine pattern. DCs from tumor bearing mice displayed also significantly less capacity to stimulate CD8+ T cells to produce IFN-. Therefore, the phenotype and function of DCs in ret transgenic mice showed the characteristics of tolerogenic DCs. Melanoma-derived factors in ret transgenic mice were demonstrated to be involved in the acquisition of tolerogenic properties, since DCs generated from bone marrow precursors in medium supplemented with mouse melanoma cell conditioned medium produced significantly less IL-12. Moreover, when activity of VEGF, IL-6, or TGF- was blocked with the respective neutralizing antibodies, IL-12 production by DCs was significantly upregulated. The p38 mitogen-activated protein kinase (MAPK) can be activated by different tumor-derived factors. A considerably elevated expression of the phosphorylated form of p38 MAPK was detected in DCs from tumor bearing mice. Suppression of p38 MAPK activity in DCs from tumor bearing mice in vitro was found to lead to normalization of their cytokine expression pattern and T-cell stimulation capacity. Taken together, constitutive activation of p38 MAPK is responsible for turning of DCs to display a tolerogenic profile in the process of melanoma development. We have demonstrated that suppression of the p38 MAPK activity in DCs from ret tumor bearing mice can reconstitute their impaired cytokine secretion pattern and ability to stimulate T cells suggesting thereby that such normalization of signaling pathways in DCs could represent an effective immunotherapeutic strategy in melanoma patients.