Vemurafenib enhances MHC induction in BRAFV600E homozygous melanoma cells

To optimally integrate targeted kinase inhibitors and immunotherapies in the treatment of melanoma, it will be critical to understand how BRAF(V600E) mutational status and BRAF(V600E) inhibition 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 BRAF(V600E)-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 gamma (IFN)gamma and IFN alpha 2b. Consistent with these findings, we observed that the forced overexpression of BRAF(V600E) has the opposite effect and can repress the baseline expression of MHC Class I molecules in A375 cells. Further studies utilitzing eight other melanoma cell lines revealed that the vemurafenib-mediated enhancement of MHC induction by IFN only occurs in the context of homozygous, but not heterozygous, BRAF(V600E) mutation. These findings suggest that BRAF(V600)Eactivity 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 BRAF(V600E) mutation, which is not routinely assessed in melanoma patients.