PMID- 16291589
OWN - NLM
STAT- MEDLINE
DCOM- 20060531
LR  - 20210206
IS  - 0006-4971 (Print)
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 107
IP  - 6
DP  - 2006 Mar 15
TI  - Tumor evasion of the immune system: inhibiting p38 MAPK signaling restores the 
      function of dendritic cells in multiple myeloma.
PG  - 2432-9
AB  - 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-beta 
      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.
FAU - Wang, Siqing
AU  - Wang S
AD  - Department of Lymphoma and Myeloma, M.D. Anderson Cancer Center, Houston, TX 
      77030, USA.
FAU - Yang, Jing
AU  - Yang J
FAU - Qian, Jianfei
AU  - Qian J
FAU - Wezeman, Michele
AU  - Wezeman M
FAU - Kwak, Larry W
AU  - Kwak LW
FAU - Yi, Qing
AU  - Yi Q
LA  - eng
GR  - CA103978/CA/NCI NIH HHS/United States
GR  - R01 CA96569/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20051115
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Culture Media, Conditioned)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Bone Marrow Cells
MH  - Cell Differentiation/immunology
MH  - Culture Media, Conditioned/pharmacology
MH  - Dendritic Cells/*immunology
MH  - Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors
MH  - *MAP Kinase Signaling System
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Multiple Myeloma/*immunology
MH  - *Tumor Escape
MH  - p38 Mitogen-Activated Protein Kinases/*antagonists & inhibitors
PMC - PMC1895733
EDAT- 2005/11/18 09:00
MHDA- 2006/06/01 09:00
PMCR- 2007/03/15
CRDT- 2005/11/18 09:00
PHST- 2005/11/18 09:00 [pubmed]
PHST- 2006/06/01 09:00 [medline]
PHST- 2005/11/18 09:00 [entrez]
PHST- 2007/03/15 00:00 [pmc-release]
AID - S0006-4971(20)65690-7 [pii]
AID - 2432 [pii]
AID - 10.1182/blood-2005-06-2486 [doi]
PST - ppublish
SO  - Blood. 2006 Mar 15;107(6):2432-9. doi: 10.1182/blood-2005-06-2486. Epub 2005 Nov 
      15.