| Abstract: | Bromodomain and extra‐terminal inhibitors (BETi) delay tumor growth, in part, through tumor cell intrinsic alterations and initiation of anti‐tumor CD8+ T‐cell responses. By contrast, BETi effects on pro‐tumoral immune responses remain unclear. Here, we show that the next‐generation BETi, PLX51107, delayed tumor growth to differing degrees in Braf V600E melanoma syngeneic mouse models. These differential responses were associated with the influx of tumor‐associated macrophages during BETi treatment. Tumors that were poorly responsive to PLX51107 showed increased influx of colony‐stimulating factor‐1 receptor (CSF‐1R)‐positive tumor‐associated macrophages. We depleted CSF‐1R+ tumor‐associated macrophages with the CSF‐1R inhibitor, PLX3397, in combination with PLX51107. Treatment with PLX3397 enhanced the efficacy of PLX51107 in poorly responsive Braf V600E syngeneic melanomas in vivo. These findings suggest that tumor‐associated macrophage accumulation limits BETi efficacy and that co‐treatment with PLX3397 can improve response to PLX51107, offering a potential novel combination therapy for metastatic melanoma patients. |
