Activation of p38 Mitogen-Activated Protein Kinase Drives Dendritic Cells to Become Tolerogenic in Ret Transgenic Mice Spontaneously Developing Melanoma

Skin Cancer Unit, German Cancer Research Center and University Hospital Mannheim, Heidelberg, Germany.
Clinical Cancer Research (Impact Factor: 8.72). 07/2009; 15(13):4382-90. DOI: 10.1158/1078-0432.CCR-09-0399
Source: PubMed


The purpose of the study was to investigate signaling molecules involved in the acquisition of tolerogenic properties by dendritic cells (DC) in ret transgenic mice with spontaneous melanoma progression and to target these molecules to overcome the barrier for effective melanoma immunotherapy.
DC functions and expression patterns of p38 mitogen-activated protein kinase (MAPK) in DCs were evaluated in a ret transgenic murine cutaneous melanoma model, which shows high similarity to human cutaneous melanoma with respect to clinical development. In contrast to transplantation melanoma models (like B16), this model allows the study of melanoma progression under conditions of natural interactions between tumor and host cells over time.
We showed a strong tumor infiltration with immature DCs and a reduction in the number of mature DCs in lymphoid organs during melanoma progression. DCs from melanoma-bearing mice secreted significantly more interleukin 10 and less interleukin 12p70, and showed a decreased capacity to activate T cells compared with DCs from tumor-free animals. Observed DC dysfunction was linked to considerable activation of p38 MAPK. Inhibition of its activity in spleen DCs from tumor-bearing mice led to normalization of their cytokine secretion pattern and T-cell stimulation capacity.
Our data show a critical role of constitutively activated p38 MAPK in the acquirement of tolerogenic pattern by DCs during melanoma progression that contributes to the suppression of antitumor T-cell immune responses. We suggest that new strategies of melanoma immunotherapy can include inhibitors of p38 MAPK activity in DCs.

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Available from: Dirk Schadendorf, Oct 13, 2015
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    • "Notably, Jackson and colleagues demonstrated that blockade of MEK 1/2 and ERK MAPK signaling restores tumor-mediated inhibition of DC function and promotes IL-12 production and Th1 T cell responses, whereas inhibition of p38 MAPK increases signal transduction through ERK 1/2 and blocks IL-12 production (17). In similar vein, p38 MAPK signaling in DC up-regulates IL-10 expression and induces tolerance in a mouse model of melanoma, resulting in suppression of anti-tumor T cell response, whereas inhibition of p38 signaling restored the ability of DC to stimulate T cell responses (18). The observation that p38 inhibition or MEK/ERK activation restores DC function in myeloma patients provides further evidence that p38 blockade may be of therapeutic benefit (19). "
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    • "In contrast, no difference was detected in the function of TAM between the cSHP-2 KO and WT mice (supplementary Fig. S5). It has been well documented that various cytokines, chemokines, and growth factors including IL-6, IL-10, TGF-β are needed to drive MDSC migration into tumor lesions and to keep their suppressive phenotype in tumor-bearing host303132. An accumulation of functionally active MDSC in melanoma lesions and lymphoid organs was reported to be strongly associated with T-cell anergy33. "
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    • "Ostrand-Rosenberg and Sinha, 2009; Ostrand-Rosenberg, 2010; Rook and Dalgleish, 2011). Using the ret transgenic mouse model, we have recently demonstrated an accumulation of various chronic inflammatory factors and MDSCs in melanoma lesions (Zhao et al., 2009; Meyer et al., 2011). In this study, we found that low-dose CP therapy induced a significantly higher production of several key inflammatory mediators, such as GM-CSF, IL-1b, IL-5, IL-10, IFN-g, and tumor necrosis factora , in skin tumors and metastatic LNs than in untreated tumorbearing animals. "
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