An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition

MAP-Kinase pathway antagonists induce profound clinical responses in advanced cutaneous melanoma. Complete remission is though rarely achieved due to the outgrowth of multiple subclones harboring a plethora of diverse mutations conferring acquired drug resistance. Prior to acquired resistance emerging, mutation-independent adaptive responses allow tumor cells to tolerate MAPK inhibition. Antagonizing these adaptive responses could allow an even deeper drug response and thereby thwart the emergence of acquired resistance. Here, we reveal that tumor associated macrophages and fibroblasts through the generation of a cytokine signaling network contribute to treatment tolerance. Factors released from melanoma cells induce IL1β synthesis by macrophages that in turn elicits CXCR2-ligand secretion from fibroblasts co-localized within inflammatory niches. This signaling network supports melanoma growth; inhibiting host IL-1R signaling in vivo significantly reduces melanoma growth. Moreover signaling from inflammatory niches is amplified in the presence of MAPK inhibitors, which can be seen in tumors from patients on treatment. As a consequence melanoma cells become, tolerant to combined BRAF/MEK inhibitors. Consequently, inhibiting IL-1R or CXCR2 signaling in vivo enhanced the efficacy of MAPK inhibitors. We conclude that melanoma inflammatory niches adapt to and confer tolerance on tumor cells toward BRAF and MEK inhibitors early during treatment.