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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2432-2439.
Prepublished online as a Blood First Edition Paper on November 15, 2005; DOI 10.1182/blood-2005-06-2486.
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IMMUNOBIOLOGY
Tumor evasion of the immune system: inhibiting p38 MAPK signaling restores the function of dendritic cells in multiple myeloma
Siqing Wang,
Jing Yang,
Jianfei Qian,
Michele Wezeman,
Larry W. Kwak, and
Qing Yi
From the Department of Lymphoma and Myeloma, Division of Cancer Medicine, and the Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
Dendritic cells (DCs) from patients with cancer are functionally defective, but the molecular mechanisms underlying these defects are poorly understood. In this study, we used the murine 5TGM1 myeloma model to examine the effects and mechanisms of tumor-derived factors on the differentiation and function of DCs. Myeloma cells or tumor culture conditioning medium (TCCM) were shown to inhibit the differentiation and function of BM-derived DCs (BMDCs), as evidenced by the down-regulated expression of DC-related surface molecules, decreased IL-12, and compromised capacity of the cells to activate allospecific T cells. Moreover, TCCM-treated BMDCs were inferior to normal BMDCs at priming tumor-specific immune responses in vivo. Neutralizing antibodies against IL-6, IL-10, and TGF- partially abrogated the effects. TCCM treatment activated p38 mitogen-activated protein kinase (MAPK) and Janus kinase (JNK) but inhibited extracellular regulated kinase (ERK). Inhibiting p38 MAPK restored the phenotype, cytokine secretion, and function of TCCM-treated BMDCs. BMDCs from cultures with TCCM and p38 inhibitor was as efficacious as normal BMDCs at inducing tumor-specific antibody, type 1 T cell, and cytotoxic T lymphocyte (CTL) responses and at prolonging mouse survival. Thus, our results suggested that tumor-induced p38 MAPK activation and ERK inhibition in DCs may be a new mechanism for tumor evasion and that regulating these pathways during DC differentiation provides new strategies for generating potent DC vaccines for immunotherapy in patients with cancer. (Blood. 2006;107:2432-2439)
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