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

BRAF and MEK inhibitor (BRAFi/MEKi) combinations are currently the standard treatment for patients with BRAF<sup>V600</sup> 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 t...

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Autores principales:	Stefanie Hoyer, Valentina Eberlein, Gerold Schuler, Carola Berking, Lucie Heinzerling, Niels Schaft, Jan Dörrie
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	vemurafenib dabrafenib cobimetinib trametinib BRAF inhibitor MEK inhibitor Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/a32262ee3d9641499f4337e4a28eb196
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spelling	oai:doaj.org-article:a32262ee3d9641499f4337e4a28eb1962021-11-11T17:22:02ZBRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation10.3390/ijms2221119511422-00671661-6596https://doaj.org/article/a32262ee3d9641499f4337e4a28eb1962021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11951https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067BRAF and MEK inhibitor (BRAFi/MEKi) combinations are currently the standard treatment for patients with BRAF<sup>V600</sup> 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<sup>+</sup> and CD4<sup>+</sup> 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<sup>+</sup> 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.Stefanie HoyerValentina EberleinGerold SchulerCarola BerkingLucie HeinzerlingNiels SchaftJan DörrieMDPI AGarticlevemurafenibdabrafenibcobimetinibtrametinibBRAF inhibitorMEK inhibitorBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11951, p 11951 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	vemurafenib dabrafenib cobimetinib trametinib BRAF inhibitor MEK inhibitor Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	vemurafenib dabrafenib cobimetinib trametinib BRAF inhibitor MEK inhibitor Biology (General) QH301-705.5 Chemistry QD1-999 Stefanie Hoyer Valentina Eberlein Gerold Schuler Carola Berking Lucie Heinzerling Niels Schaft Jan Dörrie BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation
description	BRAF and MEK inhibitor (BRAFi/MEKi) combinations are currently the standard treatment for patients with BRAF<sup>V600</sup> 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<sup>+</sup> and CD4<sup>+</sup> 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<sup>+</sup> 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.
format	article
author	Stefanie Hoyer Valentina Eberlein Gerold Schuler Carola Berking Lucie Heinzerling Niels Schaft Jan Dörrie
author_facet	Stefanie Hoyer Valentina Eberlein Gerold Schuler Carola Berking Lucie Heinzerling Niels Schaft Jan Dörrie
author_sort	Stefanie Hoyer
title	BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation
title_short	BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation
title_full	BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation
title_fullStr	BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation
title_full_unstemmed	BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation
title_sort	braf and mek inhibitors affect dendritic-cell maturation and t-cell stimulation
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a32262ee3d9641499f4337e4a28eb196
work_keys_str_mv	AT stefaniehoyer brafandmekinhibitorsaffectdendriticcellmaturationandtcellstimulation AT valentinaeberlein brafandmekinhibitorsaffectdendriticcellmaturationandtcellstimulation AT geroldschuler brafandmekinhibitorsaffectdendriticcellmaturationandtcellstimulation AT carolaberking brafandmekinhibitorsaffectdendriticcellmaturationandtcellstimulation AT lucieheinzerling brafandmekinhibitorsaffectdendriticcellmaturationandtcellstimulation AT nielsschaft brafandmekinhibitorsaffectdendriticcellmaturationandtcellstimulation AT jandorrie brafandmekinhibitorsaffectdendriticcellmaturationandtcellstimulation
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BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation

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