title: Natural killer cells are essential for the ability of BRAF inhibitors to control BRAFV600E-mutant metastatic melanoma.
abstract: BRAF(V600E) is a major oncogenic mutation found in approximately 50% of human melanoma that confers constitutive activation of the MAPK pathway and increased melanoma growth. Inhibition of BRAF(V600E) by oncogene targeting therapy increases overall survival of patients with melanoma, but is unable to produce many durable responses. Adaptive drug resistance remains the main limitation to BRAF(V600E) inhibitor clinical efficacy and immune-based strategies could be useful to overcome disease relapse. Tumor microenvironment greatly differs between visceral metastasis and primary cutaneous melanoma, and the mechanisms involved in the antimetastatic efficacy of BRAF(V600E) inhibitors remain to be determined. To address this question, we developed a metastatic BRAF(V600E)-mutant melanoma cell line and demonstrated that the antimetastatic properties of BRAF inhibitor PLX4720 (a research analogue of vemurafenib) require host natural killer (NK) cells and perforin. Indeed, PLX4720 not only directly limited BRAF(V600E)-induced tumor cell proliferation, but also affected NK cell functions. We showed that PLX4720 increases the phosphorylation of ERK1/2, CD69 expression, and proliferation of mouse NK cells in vitro. NK cell frequencies were significantly enhanced by PLX4720 specifically in the lungs of mice with BRAF(V600E) lung metastases. Furthermore, PLX4720 also increased human NK cell pERK1/2, CD69 expression, and IFNγ release in the context of anti-NKp30 and IL2 stimulation. Overall, this study supports the idea that additional NK cell-based immunotherapy (by checkpoint blockade or agonists or cytokines) may combine well with BRAF(V600E) inhibitor therapy to promote more durable responses in melanoma.
authors.affiliation: Laboratorio de Pesquisa em Células Inflamatórias e Neoplásicas Group, Universidade Federal do Paraná, Curitiba, Paraná, Brazil. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Lucas
authors.initials: L
authors.lastname: Ferrari de Andrade
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Shin F
authors.initials: SF
authors.lastname: Ngiow
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Stannard
authors.affiliation: Gustave Roussy Cancer Campus, Villejuif, France. INSERM U1015, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rusakiewicz
authors.affiliation: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Murugan
authors.initials: M
authors.lastname: Kalimutho
authors.affiliation: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.affiliation: Bone Marrow Transplant Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Siok-Keen
authors.initials: SK
authors.lastname: Tey
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Gustave Roussy Cancer Campus, Villejuif, France. INSERM U1015, Villejuif, France. Université Paris Sud-XI, Faculté de Médecine, Le Kremlin Bicêtre, France. Department of Medical Oncology, IGR, Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Martinet
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia. mark.smyth@qimrberghofer.edu.au.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000378:metabolism* / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf