title: Vemurafenib enhances MHC induction in BRAFV600Ehomozygous melanoma cells.
abstract: To optimally integrate targeted kinase inhibitors and immunotherapies in the treatment of melanoma, it will be critical to understand howBRAFV600Emutational status and BRAFV600Einhibition influence the expression of genes that govern antitumor immune responses. Because major histocompatibility complex (MHC) molecules are critical for interactions between tumor cells and lymphocytes, we investigated the impact of BRAFV600E-selective inhibitors on the expression of MHC molecules. We found that the treatment of A375 melanoma cells with vemurafenib enhances the induction of MHC Class I and Class II molecules by interferon γ and IFNα2b. Consistent with these findings, we observed that the forced overexpression of BRAFV600Ehas the opposite effect and can repress the baseline expression of MHC Class I molecules in A375 cells. Further studies utilizing eight other melanoma cell lines revealed that the vemurafenib-mediated enhancement of MHC induction by IFNγ only occurs in the context of homozygous, but not heterozygous, BRAFV600Emutation. These findings suggest thatBRAFV600Eactivity directly influences the expression of MHC molecules and the response to Type I and Type II IFNs. Furthermore, our data suggest that the effect of vemurafenib on the expression of immune system-relevant genes may depend on the zygosity of the BRAFV600Emutation, which is not routinely assessed in melanoma patients.
authors.affiliation: Department of Dermatology; Emory University School of Medicine; Atlanta, GA USA.
authors.forename: Bishu
authors.initials: B
authors.lastname: Sapkota
authors.forename: Charles E
authors.initials: CE
authors.lastname: Hill
authors.forename: Brian P
authors.initials: BP
authors.lastname: Pollack
keywords: BRAF; MHC; melanoma; vemurafenib