Reprograming of Tumor-Associated Macrophages in Human BrafV600EMutant Melanoma

Abstract

Abstract Melanoma tumors are highly immunogenic, making them an attractive target for immunotherapy. However, many patients do not mount robust clinical responses to targeted therapies, which is attributable, at least in part, to suppression of immune responses by tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Using a human in vitro culture system, we have shown that the synthetic triterpenoid CDDO-Me enhances immune activation by reprogramming macrophages from immuno-suppressive to immuno-stimulatory. CDDO-Me significantly reduced CCL2, VEGF and IL-6 secretion by macrophages and inhibited surface expression of CD163, a marker associated with poor clinical outcomes. Furthermore, CDDO-Me mediated both contact-dependent and independent effects on macrophage activation in tri-cultures of macrophages with activated autologous T cells and BRAFV600E mutant melanoma cells. Signaling pathway activation was interrogated to identify the potential mechanism by which CDDO-Me attenuates the pro-tumorigenic macrophage activation profile. Our results demonstrated that CDDO-Me inhibited STAT3 phosphorylation, which is a known regulator of TAM activation. Given these results, we hypothesize that, in addition to mediating direct anti-tumorigenic effects, CDDO-Me may also enhance the efficacy of additional immunotherapies, including BRAF inhibition. Collectively, our studies suggest that the redirection of immuno-suppressive myeloid cell activation may provide both a direct means of inhibiting melanoma growth and may enhance the efficacy of additional targeted immunotherapies through relief of immune suppression in the TME.