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BRAF inhibitors stimulate inflammasome activation and interleukin 1 beta production in dendritic cells.

ABSTRACT: Melanoma is the most dangerous form of skin cancer with a growing incidence over the last decades. Fourty percent of all melanomas harbor a mutation in the signaling adaptor BRAF (V600E) that results in ERK hyperactivity as an oncogenic driver. In these cases, treatment with the BRAF^V600E inhibitors Vemurafenib (VEM) or Dabrafenib (DAB) coapplied with the MEK1/2 inhibitors Cobimetinib (COB) or Trametinib (TRA) can result in long-term suppression of tumor growth. Besides direct suppression of ERK activity, these inhibitors have been reported to also modulate tumor immune responses, and exert pro-inflammatory side effects such as fever and rash in some patients. Here we asked for potential effects of BRAF^V600E inhibitors on dendritic cells (DC) which are essential for the induction of adaptive anti-tumor responses. Both splenic and bone marrow-derived (BM) mouse dendritic cells (DC) up-regulated costimulator expression (CD80, CD86) in response to DAB but not VEM treatment. Moreover, DAB and to lesser extent VEM enhanced IL-1? (interleukin 1 beta) release by splenic DC, and by LPS-stimulated BMDC. We demonstrate that DAB and VEM activated the NLRC4/Caspase-1 inflammasome. At high concentration, DAB also induced inflammasome activation independent of Caspase-1. TRA and COB elevated MHCII expression on BMDC, and modulated the LPS-induced cytokine pattern. Immunomodulatory activity of DAB and VEM was also observed in human monocyte-derived DC, and DAB induced IL-1? in human primary DC. Altogether, our study shows that BRAF^V600E inhibitors upregulate IL-1? release by mouse and human DC which may affect the DC-mediated course of anti-tumor immune responses.

SUBMITTER: Hajek E

PROVIDER: S-EPMC6033361 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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BRAF inhibitors stimulate inflammasome activation and interleukin 1 beta production in dendritic cells.

Hajek Eva E Krebs Franziska F Bent Rebekka R Haas Katharina K Bast Antje A Steinmetz Ivo I Tuettenberg Andrea A Grabbe Stephan S Bros Matthias M

Oncotarget 20180619 47

Melanoma is the most dangerous form of skin cancer with a growing incidence over the last decades. Fourty percent of all melanomas harbor a mutation in the signaling adaptor BRAF (V600E) that results in ERK hyperactivity as an oncogenic driver. In these cases, treatment with the BRAF<sup>V600E</sup> inhibitors Vemurafenib (VEM) or Dabrafenib (DAB) coapplied with the MEK1/2 inhibitors Cobimetinib (COB) or Trametinib (TRA) can result in long-term suppression of tumor growth. Besides direct suppres ...[more]

PMID: 29983861

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BRAF inhibitors stimulate inflammasome activation and interleukin 1 beta production in dendritic cells.

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BRAF inhibitors stimulate inflammasome activation and interleukin 1 beta production in dendritic cells.

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