Vemurafenib enhances MHC induction inBRAF^V600Ehomozygous melanoma cells

Abstract

To optimally integrate targeted kinase inhibitors and immunotherapies in the treatment of melanoma, it will be critical to understand how BRAFV600E mutational status and BRAFV600E 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 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 BRAFV600E has 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, BRAFV600E mutation. These findings suggest that BRAFV600Eactivity 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 BRAFV600E mutation, which is not routinely assessed in melanoma patients.

NLRC5/MHC class I transactivator is a target for immune evasion in cancer

“…Therapeutics augmenting NLRC5 activity could compensate for this deficit by breaking cancer immune evasion in a broad range of tumor types. Interestingly, it has been reported that currently used therapies, such as an EGF receptor inhibitor (cetuximab) or a B-Raf inhibitor (vemurafenib), enhance MHC class I expression via IFN-γ (35,36). Therefore, these currently available therapies, originally designed to disrupt oncogenic signaling, may mediate their effects in part via the NLRC5-dependent MHC class I pathway.…”

Immune Checkpoint Inhibitors in the Treatment of Melanoma: From Basic Science to Clinical Application

“…Molecularly targeted agents are also being combined with immune checkpoint inhibitors. BRAF inhibition, which is FDA-approved for the treatment of metastatic melanoma expressing the activating BRAF V600E mutation, has been shown to increase MHC expression, tumor antigen presentation, and T-cell infiltration (98)(99)(100)(101)(102). Similarly, MEK inhibitors have been shown to improve CD8+ T-cell activity in preclinical models in combination with PD-1 blockade (103).…”

Trial Watch: Peptide-based anticancer vaccines

“…C recurrent Grade II gliomas (NCT02193347); (6) the safety and efficacy of peptides derived from indoleamine 2,3-dioxygenase 1 (IDO1) [202][203][204][205][206] combined with the FDA-approved immune checkpoint blocker ipilimumab (also known as Yervoy TM ) [207][208][209][210][211][212] and vemurafenib (an FDA-approved inhibitor of mutant BRAF) [213][214][215][216][217] are being evaluated in melanoma patients (NCT02077114); (7) the therapeutic profile of a CMP targeting ganglioside GD2 and the so-called Lewis Y antigen (2 non-peptide TAAs), [218][219][220] employed as a PADRE-and Montanide ISA-51-adjuvanted intervention in combination with standard chemotherapy, is being assessed in breast carcinoma patients (NCT02229084); (8) full-length, recombinant cancer/ testis antigen 1B (CTAG1B, best known as NY-ESO-1)…”