Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 21, Pages -Publisher
MDPI
DOI: 10.3390/ijms222111951
Keywords
vemurafenib; dabrafenib; cobimetinib; trametinib; BRAF inhibitor; MEK inhibitor; DCs; T cells; immunotherapy; melanoma
Funding
- Verein zur Foerderung des Tumorzentrums der Universitaet Erlangen-Nuernberg e.V
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This study investigated the impact of BRAFi/MEKi on the maturation of monocyte-derived dendritic cells (moDCs) and their interaction with T cells. The findings showed that these inhibitors altered cytokine secretion and surface marker expression of DCs, leading to lower activation markers and cytokine secretion in T cells during antigen-specific stimulation。
BRAF and MEK inhibitor (BRAFi/MEKi) combinations are currently the standard treatment for patients with BRAF(V600) 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.
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