Inhibition of both BRAF and MEK in BRAF V600E mutant melanoma restores compromised dendritic cell (DC) function while ha
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ORIGINAL ARTICLE
Inhibition of both BRAF and MEK in BRAFV600E mutant melanoma restores compromised dendritic cell (DC) function while having differential direct effects on DC properties Patrick A. Ott • Trevor Henry • Sonja Jimenez Baranda Davor Frleta • Olivier Manches • Dusan Bogunovic • Nina Bhardwaj
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Received: 31 August 2012 / Accepted: 13 December 2012 / Published online: 10 January 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose Dendritic cells (DCs) can induce strong tumorspecific T-cell immune responses. Constitutive upregulation of the mitogen-activated protein kinase (MAPK) pathway by a BRAFV600 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 BRAFV600 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-a) 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
Electronic supplementary material The online version of this article (doi:10.1007/s00262-012-1389-z) contains supplementary material, which is available to authorized users. P. A. Ott T. Henry S. J. Baranda D. Frleta O. Manches D. Bogunovic N. Bhardwaj (&) New York University Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1303, New York, NY 10016, USA e-mail: [email protected] P. A. Ott e-mail: [email protected]
vemurafenib only in melanoma cell lines carrying a BRAFV600E 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 BRAFV600E 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. Keywords Dendritic cell Melanoma BRAF MEK Immune suppression Tumor microenvironment
Introduction Metastatic melanoma is an aggressive skin cancer that is largely resistant to treatment with systemic chemotherapy. Recent advances with targeted agents that block driver oncogenic mutations such as BRAFV600E/
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