The Immune Microenvironment Confers Resistance to MAPK Pathway Inhibitors through Macrophage-Derived TNFα

Recently, the rationale for combining targeted therapy with immunotherapy has come to light, but our understanding of the immune response during MAPK pathway inhibitor treatment is limited. We discovered that the immune microenvironment can act as a source of resistance to MAPK pathway-targeted therapy, and moreover during treatment this source becomes reinforced. In particular, we identified macrophage-derived TNF alpha as a crucial melanoma growth factor that provides resistance to MAPK pathway inhibitors through the lineage transcription factor MITF (microphthalmia transcription factor). Most strikingly, in BRAF-mutant melanomas of patients and BRAF(V600E) melanoma allografts, MAPK pathway inhibitors increased the number of tumor-associated macrophages, and TNF alpha and MITF expression. Inhibiting TNF alpha signaling with I kappa B kinase inhibitors profoundly enhanced the efficacy of MAPK pathway inhibitors by targeting not only the melanoma cells but also the microenvironment. In summary, we identify the immune microenvironment as a novel source of resistance and reveal a new strategy to improve the efficacy of targeted therapy in melanoma. SIGNIFICANCE: This study identifies the immune microenvironment as a source of resistance to MAPK pathway inhibitors through macrophage-derived TNF alpha, and reveals that in patients on treatment this source becomes reinforced. Inhibiting I kappa B kinase enhances the efficacy of MAPK pathway inhibitors, which identifies this approach as a potential novel strategy to improve targeted therapy in melanoma. (C) 2014 AACR.