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, Qing Yi

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

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-β 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.

Original languageEnglish (US)
Pages (from-to)2432-2439
Number of pages8
JournalBlood
Volume107
Issue number6
DOIs
StatePublished - Mar 15 2006

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Tumor evasion of the immune system: Inhibiting p38 MAPK signaling restores the function of dendritic cells in multiple myeloma'. Together they form a unique fingerprint.

Cite this