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Article

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,*,‡
1
Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Hartmannstraße 14, 91052 Erlangen, Germany
2
Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), Östliche Stadtmauerstraße 30, 91054 Erlangen, Germany
3
Deutsches Zentrum Immuntherapie (DZI), Ulmenweg 18, 91054 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
5
Department of Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany
6
Unit Preclinical Validation, Department of Vaccines and Infection Models, Fraunhofer Institute for Cell Therapy and Immunology, IZI, Perlickstraße 1, 40103 Leipzig, Germany
7
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; https://doi.org/10.3390/ijms222111951
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. https://doi.org/10.3390/ijms222111951

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. https://doi.org/10.3390/ijms222111951

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. https://doi.org/10.3390/ijms222111951

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