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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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Submitted June 22, 2005
Accepted November 2, 2005
Tumor evasion of the immune system: inhibiting P38 map kinase signaling restores the function of dendritic cells in multiple myeloma
Siqing Wang, Jing Yang, Jianfei Qian, Michele Wezeman, Larry W Kwak, and Qing Yi*
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, USA
* Corresponding author; email: qyi{at}mdanderson.org.
DCs from cancer patients are functionally defective, however, molecular mechanisms underlying are poorly understood. In this study, we used the murine 5TGM1 myeloma model to examine the effects and mechanism of tumor-derived factors on the differentiation and function of DCs. Myeloma cells or tumor culture conditioning medium (TCCM) were shown to inhibit differentiation and function of BM-derived DCs (BMDCs), evidenced by the downregulated 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 Abs against IL-6, IL-10, and TGF- partially abrogated the effects. TCCM treatment activated p38 MAPK and JNK but inhibited ERK. Inhibiting p38 MAPK restored the phenotype, cytokine secretion, and function of TCCM-treated BMDCs. BMDCs from cultures with both TCCM and p38 inhibitor was as efficacious as normal BMDCs at inducing tumor-specific Ab, type-1 T-cell, and CTL responses, and prolonging mouse survival. Thus, our results suggest that tumor-induced p38 MAPK activation and ERK inhibition in DCs may be a new mechanism for tumor evasion, and regulating these pathways during DC differentiation provides new strategies for generating potent DC vaccines for immunotherapy in cancer patients.
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