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

Abstract

// Eva Hajek 1 , Franziska Krebs 1 , Rebekka Bent 1 , Katharina Haas 1 , Antje Bast 2 , Ivo Steinmetz 2 , Andrea Tuettenberg 1 , Stephan Grabbe 1, * and Matthias Bros 1, * 1 Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany 2 Friedrich Loeffler Institute of Medical Microbiology, University Medicine Greifswald, Greifswald, Germany * These authors contributed eqully to this work Correspondence to: Stephan Grabbe, email: stephan.grabbe@unimedizin-mainz.de Keywords: BRAF V600E inhibitor; MEK inhibitor; dendritic cell; IL-1beta; inflammasome; Immunology Received: September 19, 2017      Accepted: May 13, 2018      Published: June 19, 2018 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-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 BRAF V600E inhibitors upregulate IL-1β release by mouse and human DC which may affect the DC-mediated course of anti-tumor immune responses.