Vemurafenib enhances MHC induction in BRAF(V600E) homozygous melanoma cells.

摘要

To optimally integrate targeted kinase inhibitors and immunotherapies in thetreatment of melanoma, it will be critical to understand how BRAF(V600E)mutational status and BRAF(V600E) inhibition influence the expression of genesthat govern antitumor immune responses. Because major histocompatibility complex (MHC) molecules are critical for interactions between tumor cells andlymphocytes, we investigated the impact of BRAF(V600E)-selective inhibitors onthe expression of MHC molecules. We found that the treatment of A375 melanomacells with vemurafenib enhances the induction of MHC Class I and Class IImolecules by interferon γ and IFNα2b. Consistent with these findings, we observedthat the forced overexpression of BRAF(V600E) has the opposite effect and canrepress the baseline expression of MHC Class I molecules in A375 cells. Furtherstudies utilizing eight other melanoma cell lines revealed that thevemurafenib-mediated enhancement of MHC induction by IFNγ only occurs in thecontext of homozygous, but not heterozygous, BRAF(V600E) mutation. These findingssuggest that BRAF(V600E) activity directly influences the expression of MHCmolecules and the response to Type I and Type II IFNs. Furthermore, our datasuggest that the effect of vemurafenib on the expression of immunesystem-relevant genes may depend on the zygosity of the BRAF(V600E) mutation,which is not routinely assessed in melanoma patients.