PMID- 23306863
OWN - NLM
STAT- MEDLINE
DCOM- 20130607
LR  - 20240426
IS  - 1432-0851 (Electronic)
IS  - 0340-7004 (Print)
IS  - 0340-7004 (Linking)
VI  - 62
IP  - 4
DP  - 2013 Apr
TI  - Inhibition of both BRAF and MEK in BRAF(V600E) mutant melanoma restores 
      compromised dendritic cell (DC) function while having differential direct effects 
      on DC properties.
PG  - 811-22
LID - 10.1007/s00262-012-1389-z [doi]
AB  - PURPOSE: Dendritic cells (DCs) can induce strong tumor-specific T-cell immune 
      responses. Constitutive upregulation of the mitogen-activated protein kinase 
      (MAPK) pathway by a BRAF(V600) mutation, which is present in about 50 % of 
      metastatic melanomas, may be linked to compromised function of DCs in the tumor 
      microenvironment. Targeting both MEK and BRAF has shown efficacy in BRAF(V600) 
      mutant melanoma. METHODS: We co-cultured monocyte-derived human DCs with melanoma 
      cell lines pretreated with the MEK inhibitor U0126 or the BRAF inhibitor 
      vemurafenib. Cytokine production (IL-12 and TNF-alpha) and surface marker expression 
      (CD80, CD83, and CD86) in DCs matured with the Toll-like receptor 3/Melanoma 
      Differentiation-Associated protein 5 agonist polyI:C was examined. Additionally, 
      DC function, viability, and T-cell priming capacity were assessed upon direct 
      exposure to U0126 and vemurafenib. RESULTS: Cytokine production and 
      co-stimulation marker expression were suppressed in polyI:C-matured DCs exposed 
      to melanoma cells in co-cultures. This suppression was reversed by MAPK blockade 
      with U0126 and/or vemurafenib only in melanoma cell lines carrying a BRAF(V600E) 
      mutation. Furthermore, when testing the effect of U0126 directly on DCs, marked 
      inhibition of function, viability, and DC priming capacity was observed. In 
      contrast, vemurafenib had no effect on DC function across a wide range of dose 
      concentrations. CONCLUSIONS: BRAF(V600E) mutant melanoma cells modulate DC 
      through the MAPK pathway as its blockade can reverse suppression of DC function. 
      MEK inhibition negatively impacts DC function and viability if applied directly. 
      In contrast, vemurafenib does not have detrimental effects on important functions 
      of DCs and may therefore be a superior candidate for combination immunotherapy 
      approaches in melanoma patients.
FAU - Ott, Patrick A
AU  - Ott PA
AD  - New York University Cancer Institute, New York University School of Medicine, 522 
      First Avenue, SRB 1303, New York, NY, 10016, USA. patrick_ott@dfci.harvard.edu
FAU - Henry, Trevor
AU  - Henry T
FAU - Baranda, Sonja Jimenez
AU  - Baranda SJ
FAU - Frleta, Davor
AU  - Frleta D
FAU - Manches, Olivier
AU  - Manches O
FAU - Bogunovic, Dusan
AU  - Bogunovic D
FAU - Bhardwaj, Nina
AU  - Bhardwaj N
LA  - eng
PT  - Journal Article
DEP - 20130110
PL  - Germany
TA  - Cancer Immunol Immunother
JT  - Cancer immunology, immunotherapy : CII
JID - 8605732
RN  - 0 (Antigens, CD)
RN  - 0 (B7-1 Antigen)
RN  - 0 (Butadienes)
RN  - 0 (CD40 Antigens)
RN  - 0 (Cytokines)
RN  - 0 (Immunoglobulins)
RN  - 0 (Indoles)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Nitriles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Sulfonamides)
RN  - 0 (U 0126)
RN  - 207SMY3FQT (Vemurafenib)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - O84C90HH2L (Poly I-C)
SB  - IM
MH  - Antigens, CD/biosynthesis/immunology
MH  - B7-1 Antigen/biosynthesis/immunology
MH  - Butadienes/pharmacology
MH  - CD40 Antigens/biosynthesis/immunology
MH  - Cell Line, Tumor
MH  - Coculture Techniques
MH  - Cytokines/biosynthesis/immunology
MH  - Dendritic Cells/*immunology
MH  - Humans
MH  - Immunoglobulins/biosynthesis/immunology
MH  - Indoles/pharmacology
MH  - MAP Kinase Kinase Kinases/*antagonists & inhibitors/immunology
MH  - MAP Kinase Signaling System/drug effects/immunology
MH  - Melanoma/*enzymology/genetics/*immunology
MH  - Membrane Glycoproteins/biosynthesis/immunology
MH  - Mutation
MH  - Nitriles/pharmacology
MH  - Poly I-C/immunology
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins B-raf/*antagonists & inhibitors/genetics/immunology
MH  - Sulfonamides/pharmacology
MH  - T-Lymphocytes/immunology
MH  - Vemurafenib
MH  - CD83 Antigen
PMC - PMC11028975
COIS- The authors declare that they have no conflict of interest.
EDAT- 2013/01/12 06:00
MHDA- 2013/06/08 06:00
PMCR- 2013/01/10
CRDT- 2013/01/12 06:00
PHST- 2012/08/31 00:00 [received]
PHST- 2012/12/13 00:00 [accepted]
PHST- 2013/01/12 06:00 [entrez]
PHST- 2013/01/12 06:00 [pubmed]
PHST- 2013/06/08 06:00 [medline]
PHST- 2013/01/10 00:00 [pmc-release]
AID - 1389 [pii]
AID - 10.1007/s00262-012-1389-z [doi]
PST - ppublish
SO  - Cancer Immunol Immunother. 2013 Apr;62(4):811-22. doi: 10.1007/s00262-012-1389-z. 
      Epub 2013 Jan 10.