Activation of p38 mitogen-activated protein kinase drives dendritic cells to become tolerogenic in ret transgenic mice spontaneously developing melanoma.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Zhao
Fang
F
Skin Cancer Unit, German Cancer Research Center and University Hospital Mannheim, Heidelberg, Germany.
Falk
Christine
C
Osen
Wolfram
W
Kato
Masashi
M
Schadendorf
Dirk
D
Umansky
Viktor
V
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation / Q000502:physiology; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D047368:Tumor Burden / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*
D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases