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BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation

by 1,2,3,4, 1,2,3,5,6,†, 1,2,3, 1,2,3, 1,2,3,7, 1,2,3,*,‡ and 1,2,3,*,‡
Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Hartmannstraße 14, 91052 Erlangen, Germany
Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), Östliche Stadtmauerstraße 30, 91054 Erlangen, Germany
Deutsches Zentrum Immuntherapie (DZI), Ulmenweg 18, 91054 Erlangen, Germany
Department of Palliative Medicine, Universitätsklinikum Erlangen, Comprehensive Cancer Center CCC Erlangen-EMN, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Krankenhausstraße 12, 91054 Erlangen, Germany
Department of Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany
Unit Preclinical Validation, Department of Vaccines and Infection Models, Fraunhofer Institute for Cell Therapy and Immunology, IZI, Perlickstraße 1, 40103 Leipzig, Germany
Department of Dermatology and Allergy, University Hospital, LMU Munich, 80539 Munich, Germany
Authors to whom correspondence should be addressed.
A part of the present work was performed in fulfillment of the requirements for obtaining the degree of B.Sc. at the Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) by Valentina Eberlein.
These authors contributed equally to this work.
Academic Editor: Atsushi Matsuzawa
Int. J. Mol. Sci. 2021, 22(21), 11951;
Received: 7 October 2021 / Revised: 29 October 2021 / Accepted: 1 November 2021 / Published: 4 November 2021
(This article belongs to the Special Issue Kinase Signal Transduction 2.0)
BRAF and MEK inhibitor (BRAFi/MEKi) combinations are currently the standard treatment for patients with BRAFV600 mutant metastatic melanoma. 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. 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. DCs matured in the presence of vemurafenib or vemurafenib/cobimetinib altered their cytokine secretion and surface marker expression profile. 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. 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. T-helper cell/DC interaction is a bi-directional process that normally results in DC activation. Vemurafenib and vemurafenib/cobimetinib completely abolished the helper T-cell-mediated upregulation of CD70, CD80, and CD86 but not CD25 on the DCs. The combination of dabrafenib/trametinib affected DC maturation and activation as well as T-cell activation less than combined vemurafenib/cobimetinib did. Hence, for a potential combination with immunotherapy, our data indicate the superiority of dabrafenib/trametinib treatment. View Full-Text
Keywords: vemurafenib; dabrafenib; cobimetinib; trametinib; BRAF inhibitor; MEK inhibitor; DCs; T cells; immunotherapy; melanoma vemurafenib; dabrafenib; cobimetinib; trametinib; BRAF inhibitor; MEK inhibitor; DCs; T cells; immunotherapy; melanoma
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MDPI and ACS Style

Hoyer, S.; Eberlein, V.; Schuler, G.; Berking, C.; Heinzerling, L.; Schaft, N.; Dörrie, J. BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation. Int. J. Mol. Sci. 2021, 22, 11951.

AMA Style

Hoyer S, Eberlein V, Schuler G, Berking C, Heinzerling L, Schaft N, Dörrie J. BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation. International Journal of Molecular Sciences. 2021; 22(21):11951.

Chicago/Turabian Style

Hoyer, Stefanie, Valentina Eberlein, Gerold Schuler, Carola Berking, Lucie Heinzerling, Niels Schaft, and Jan Dörrie. 2021. "BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation" International Journal of Molecular Sciences 22, no. 21: 11951.

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