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BRAF and MEK inhibitors affect dendritic-cell maturation and t-cell stimulation

: Hoyer, Stefanie; Eberlein, Valentina; Schuler, Gerold; Berking, Carola; Heinzerling, Lucie; Schaft, Niels; Dörrie, Jan

Volltext ()

International journal of molecular sciences 22 (2021), Nr.21, Art. 11951, 23 S.
ISSN: 1422-0067
ISSN: 1661-6596
Zeitschriftenaufsatz, Elektronische Publikation
Fraunhofer IZI ()
Vemurafenib; Dabrafenib; Cobimetinib; Trametinib; BRAF inhibitor; MEK inhibitor; DCs; CAR-T-Zelle; Immuntherapie; melanoma

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. Vemurafeniband 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/cobimetinibdid. Hence, for a potential combination with immunotherapy, our data indicate the superiority of dabrafenib/trametinib treatment.