Natural killer cells are essential for the ability of BRAF inhibitors to control BRAFV600E mutant metastatic melanoma
Menée in vitro et in vivo, cette étude met en évidence le rôle joué par les lymphocytes NK dans la réponse à un traitement par inhibiteur de BRAF, ce qui suggère l'intérêt d'une immunothérapie complémentaire pour le traitement des patients atteints d'un mélanome métastatique présentant la mutation V600E du gène BRAF
BRAFV600E 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 BRAFV600E by oncogene targeting therapy increases overall survival of melanoma patients, but is unable to produce many durable responses. Adaptive drug resistance remains the main limitation to BRAFV600E 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 the anti-metastatic efficacy of BRAFV600E inhibitors remain to be determined. To address this question, we developed a metastatic BRAFV600E mutant melanoma cell line and demonstrated that the anti-metastatic properties of BRAF inhibitor PLX4720 (a research analogue of Vemurafenib) require host NK cells and perforin. Indeed, PLX4720 was not only directly limiting BRAFV600E-induced tumor cell proliferation, but was also impacting upon 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 BRAFV600E lung metastases. Furthermore, PLX4720 also increased human NK cell pERK1/2, CD69 expression, and IFN-γ release in the context of anti-NKp30 and IL-2 stimulation. Overall, this study supports the idea that additional NK cell-based immunotherapy (by checkpoint blockade or agonists or cytokines) may combine well with BRAFV600E inhibitor therapy to promote more durable responses in melanoma.
Cancer Research 2014