Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAF V600E Melanoma Lines with Vemurafenib

Abstract : Over 60% of human melanoma tumors bear a mutation in the BRAF gene. The most frequent mutation is a substitution at codon 600 (V600E), leading to a constitutively active BRAF and over-activation of the MAPK pathway. Patients harboring mutated BRAF respond to kinase inhibitors such as vemurafenib. However, these responses are transient, and relapses are frequent. Melanoma cells are efficiently lysed by activated natural killer (NK) cells. Melanoma cells express several stress-induced ligands that are recognized by activating NK-cell receptors. We have investigated the effect of vemurafenib on the immunogenicity of seven BRAF-mutated melanoma cells to NK cells and on their growth and sensitivity to NK-cell–mediated lysis. We showed that vemurafe-nib treatment modulated expression of ligands for two activating NK receptors, increasing expression of B7-H6, a ligand for NKp30, and decreasing expression of MICA and ULBP2, ligands for NKG2D. Vemurafenib also increased expression of HLA class I and HLA-E molecules, likely leading to higher engagement of inhibitory receptors (KIRs and NKG2A, respectively), and decreased lysis of vemurafenib-treated melanoma cell lines by cytokine-activated NK cells. Finally, we showed that whereas batimastat (a broad-spectrum matrix metalloprotease inhibitor) increased cell surface ULBP2 by reducing its shedding, vemurafe-nib lowered soluble ULBP2, indicating that BRAF signal inhibition diminished expression of both cell-surface and soluble forms of NKG2D ligands. Vemurafenib, inhibiting BRAF signaling, shifted the balance of activatory and inhibitory NK ligands on melanoma cells and displayed immunoregulatory effects on NK-cell functional activities.
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Cancer Immunology Research - Cancer Immunol Res, Philadelphia, PA : American Association for Cancer Research, [2013]-, 2017, 5 (7), pp.582 - 593. 〈10.1158/2326-6066.CIR-16-0380〉
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Alexandra Frazao, Marina Colombo, Emmanuelle Fourmentraux-Neves, Meriem Messaoudene, Sylvie Rusakiewicz, et al.. Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAF V600E Melanoma Lines with Vemurafenib. Cancer Immunology Research - Cancer Immunol Res, Philadelphia, PA : American Association for Cancer Research, [2013]-, 2017, 5 (7), pp.582 - 593. 〈10.1158/2326-6066.CIR-16-0380〉. 〈inserm-01637027〉

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