696 MAPK inhibition synergizes with TNF-alpha to promote the expression of STAT1, IRF-1 and MHC class I

B.P Pollack,Y Chang

doi:10.1016/j.jid.2020.03.708

B.P Pollack, Y Chang

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https://doi.org/10.1016/j.jid.2020.03.708

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Journal: Journal of Investigative Dermatology	Publication Date: Jun 16, 2020
License type: publisher-specific-oa

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Molecular events that activate the MAPK signaling pathway are key events in melanoma pathogenesis and MAPK inhibitors (MAPKIs) such as those targeting BRAFV600E and MEK1/2 are currently in use to treat melanoma patients. In addition to their effects on tumor cell proliferation and survival, MAPKIs can increase T cell infiltration into tumors and MHC expression and clinical trials combining MAPKIs with immune-based therapies are currently being performed. TNF-alpha is a pleiotropic cytokine that plays a complex role in melanoma and has been shown to block apoptosis induced by MAPKIs. In contrast, the interplay between TNF-alpha and MAPKI-mediated immune effects are largely undefined. To further interrogate interactions between TNF-alpha and MAPKIs, we treated human melanoma cell lines with the BRAFV600E inhibitor vemurafenib or the MEK1/2 inhibitor trametinib alone or in the presence of TNF-alpha. Using A375 and HT-144 cells as models for BRAF mutant melanoma, we found that MAPKIs synergized with TNF-alpha to increasing MHC class I surface levels > 20 fold. In addition, cell surface levels of programmed death ligand 2 (PD-L2) were also increased by the combination of TNF-alpha and a MAPKI. Additional studies determined that these changes were associated with increases in steady state mRNA levels and total protein levels of MHC class I genes HLA-A, B and C . To define the mechanisms involved in this synergistic response, we examined levels of STAT1 and found that the combination of TNF-alpha and a MAPKI increased levels of STAT1 mRNA by roughly 10 fold and that of STAT1 protein by 4-5 fold. Increases in phospho-STAT1-Y701 and S727 were also observed. Similar increases were seen in levels of IRF-1 mRNA and protein. These studies suggest that MAPKIs can influence the cellular responses to TNF-alpha in a manner that promotes the expression of genes typical of an interferon signature.

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