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 BRAFV600E 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 BRAFV600E 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-1β (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-1β in human primary DC. Altogether, our study shows that BRAFV600E inhibitors upregulate IL-1β release by mouse and human DC which may affect the DC-mediated course of anti-tumor immune responses.

Highlights

  • Until a few years ago, no effective drug was available for treatment of metastatic melanoma

  • We show that DAB alone partially activated splenic and bone marrow-derived (BM) mouse dendritic cells (DCs) as reflected by elevated costimulator expression (CD80, CD86) and strongly increased IL-1β levels

  • BRAFV600E inhibitors are commonly coapplied with an assigned MEK1/2 inhibitor to efficiently block extracellular signal regulated kinase (ERK) signaling in tumor cells and to provide development of resistance mechanisms

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Summary

Introduction

Until a few years ago, no effective drug was available for treatment of metastatic melanoma. This situation changed with the introduction of immunotherapeutics and targeted therapies for melanoma treatment, including antibody-based immunotherapeutic approaches that block the inhibitory CTLA4-CD80/CD86 and PD1-PD-L1 signaling axes apparent in all types of tumor progression Mutagenome analysis identified a common point mutation within the BRAF (v-Raf murine sarcoma viral oncogene homolog B) protein (BRAFV600E) apparent in >40% of all melanoma cases [2]. BRAF serves as an adaptor kinase in the ERK (extracellular signalregulated kinases) pathway that transmits stimulatory signals of receptor binding growth factors [3]. In case of BRAFV600E, autoinhibiton of www.oncotarget.com

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