Natural killer recognition of primary melanoma cells treated with BRAFV600E inhibitor is favored by heme oxygenase 1 down-regulation

Cell redox balance is crucially driven by heme oxygenase 1 (HO-1) activity. HO-1 up-regulation has been correlated with the gain of resistance to therapy in different types of cancers and its involvement in cancer immune-escape has been hypothesized. We have investigated the role of HO-1 expression in Vemurafenib/PLX4032 (PLX)-treated BRAFV600E melanoma cells (MeOV-1) in modulating natural killer (NK) degranulation and killing. MeOV-1 cell exposure to 1–10 µM PLX4032, which efficiently reduced ERK phosphorylation, was able to induce only a slight decrease of cell viability, while HO-1 expression was upregulated. Moreover, NK cells degranulation and killing activity was decreased upon interaction with MeOV-1 exposed to PLX4032. HO-1 silencing was able to induce a mild but significant reduction of PLX-treated MeOV-1 viability and to completely restore NK ability to degranulate and their cytolytic activity. We provided evidence that HO-1 up-regulation induced by PLX4032 down-regulated B7H6 and ULBP3 expression on MeOV-1 cell surface since HO-1 silencing was able to restore their expression. Our results indicate that HO-1 down-regulation can improve the efficacy of PLX4032 favoring the degranulation and increasing killing activity of NK cells.