Tumor Evasion of the Immune System: Inhibiting p38 MAP Kinase Signaling Restores the Function of Dendritic Cells

Dendritic cells (DCs) from cancer patients are functionally defective, however, molecular mechanisms underlying are still poorly understood. In this study, we used the murine 5TGM1 myeloma model to examine the effect and mechanism of tumor-derived factors on the differentiation and function of DCs. Myeloma cells (5TGM1) 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 but increased IL-10 secretion, and compromised capacity of the cells to activate allospecific T cells in vitro. Similar results were obtained with other murine myeloma cells MOPC-315 and MPC-11. Moreover, TCCM-treated BMDCs were inferior to normal BMDCs at priming tumor-specific humoral and cellular immune responses in vivo (in the 5TGM1 mouse model). Neutralizing antibodies against IL-6, IL-10, and TGF-β partially abrogated the effects. TCCM treatment activated p38 mitogen-activated protein kinase (MAPK) and JNK but inhibited extracellular signal-related kinase (ERK). Inhibiting p38 MAPK by three different specific inhibitors was found to restore the phenotype, cytokine secretion, and function of TCCM-treated BMDCs. Vaccinating mice with BMDCs obtained from cultures in which both TCCM and p38 inhibitor were added was as efficacious as normal BMDCs at inducing tumor-specific antibody, type-1 (IFN-γ) T-cell, and CTL responses. 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 signaling pathways in vivo or during DC differentiation may provide new strategies for generating potent DC vaccines for immunotherapy of multiple myeloma and other tumors.