monocyte-derived DCs in patients with multiple myeloma
were considerably impaired and that they could be restored
by inhibiting p38 MAPK activity in progenitor cells. In
addition, suppression of p38 MAPK signaling in murine DCs
was reported to enhance their ability for IL-12 production,
to attenuate regulatory –T-cell induction, and to stimulate
the antitumor therapeutic efficacy of DCs pulsed with tumor
antigens (46). Application of p38 MAPK inhibitors for
melanoma immunotherapy in vivo will require a thorough
examination of their effects on host– T-cell antitumor
reactions because the role of p38 MAPK in these cells is
not completely clear. Whereas p38 activation was shown to
be important for T-cell development and effector functions
(47), other publications showed that p38 activity was a
prerequisite for the regulatory – T-cell stimulation (48) or for
T-cell death (49). The antitumor effects of
the p38 MAPK inhibitor in ret transgenic melanoma model
in vivo are currently under investigation.
In conclusion, our findings provide evidence that consti-
tutive activation of p38 MAPK is responsible for turning of
DCs to display a tolerogenic profile during melanoma
progression. We showed that suppression of p38 MAPK
activity in DCs from ret tumor-bearing mice could recon-
stitute their impaired cytokine secretion and ability to
stimulate T cells, suggesting thereby that such normalization
of signaling pathways in DCs can represent an effective
immunotherapeutic strategy in melanoma patients.
Disclosure of Potential Conflicts of Interests
No potential conflicts of interest were disclosed.
We thank Izumi Nakashima for initially providing ret transgenic mice, Bernd
Arnold for providing OT-I mice, Axel Benner for help with the statistical analysis,
and Kathrin Frank for excellent technical assistance.
Tolerogenic Dendritic Cells i nTransgenic Mice with Melanoma
www.aacrjournals.org Clin Cancer Res 2009;15(13) July 1, 20094389
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