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*** p ≤ 0.001, **** p ≤ 0.0001, ns: p > 0.05.īRAF and MEK inhibitors do not affect T-cell avidity: CD8 + T cells were electroporated with RNA coding for a gp100-specific T-cell receptor (TCR). In the Dunnett’s multiple comparisons test, all conditions were tested against the solvent control DMSO. p-values were determined by one-way ANOVA. Cytokine concentrations, analyzed by Cytometric Bead Array, of eight DC batches (represented by different symbols) of six donors (DC batches of the same donor, but generated in independent experiments, have the same symbol but a different color) assessed in independent experiments, are depicted. Cells were additionally treated without inhibitor (no inhib), with solvent control (DMSO), vemurafenib (V), dabrafenib (D), trametinib (T), cobimetinib (C), or the clinically used combinations V + C (VC) or D + T (DT). On day 6, cells were matured with IL-6, IL-1β, TNF, and PGE 2. MoDCs secrete IL-8, IL-10, and IL-12p70 upon treatment with vemurafenib during cytokine-induced maturation: moDCs were generated by plastic adherence, applying IL-4 and GM-CSF on days 1, 3, and 5. Hence, for a potential combination with immunotherapy, our data indicate the superiority of dabrafenib/trametinib treatment.īRAF inhibitor DCs MEK inhibitor T cells cobimetinib dabrafenib immunotherapy melanoma trametinib vemurafenib. The combination of dabrafenib/trametinib affected DC maturation and activation as well as T-cell activation less than combined vemurafenib/cobimetinib did. Vemurafenib and vemurafenib/cobimetinib completely abolished the helper T-cell-mediated upregulation of CD70, CD80, and CD86 but not CD25 on the DCs. T-helper cell/DC interaction is a bi-directional process that normally results in DC activation. However, treatment with any of the inhibitors alone or in combination did not change the avidity of CD8 + T cells in peptide titration assays with T2.A1 cells. Upon the antigen-specific stimulation of CD8 + and CD4 + T cells with these DCs or with T2.A1 cells in the presence of BRAFi/MEKi, we detected a lower expression of activation markers on and a lower cytokine secretion by these T cells.
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DCs matured in the presence of vemurafenib or vemurafenib/cobimetinib altered their cytokine secretion and surface marker expression profile. Therefore, we examined the influence of BRAFi/MEKi, either as single agent or in combination, on the maturation of monocyte-derived dendritic cells (moDCs) and their interaction with T cells. Since the RAS/RAF/MEK/ERK-pathway is crucial for the function of different immune cells, we postulated an effect on their function and thus interference with anti-tumor immunity. 7 Department of Dermatology and Allergy, University Hospital, LMU Munich, 80539 Munich, Germany.īRAF and MEK inhibitor (BRAFi/MEKi) combinations are currently the standard treatment for patients with BRAF V600 mutant metastatic melanoma.6 Unit Preclinical Validation, Department of Vaccines and Infection Models, Fraunhofer Institute for Cell Therapy and Immunology, IZI, Perlickstraße 1, 40103 Leipzig, Germany.5 Department of Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany.4 Department of Palliative Medicine, Universitätsklinikum Erlangen, Comprehensive Cancer Center CCC Erlangen-EMN, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Krankenhausstraße 12, 91054 Erlangen, Germany.3 Deutsches Zentrum Immuntherapie (DZI), Ulmenweg 18, 91054 Erlangen, Germany.2 Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), Östliche Stadtmauerstraße 30, 91054 Erlangen, Germany.1 Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Hartmannstraße 14, 91052 Erlangen, Germany.