Journal
PIGMENT CELL & MELANOMA RESEARCH
Volume 33, Issue 2, Pages 372-377Publisher
WILEY
DOI: 10.1111/pcmr.12845
Keywords
BET inhibitor; CSF-1R inhibitor; melanoma; tumor-associated macrophages
Categories
Funding
- NCI [P01 CA114046]
- National Institutes of Health (NIH) [R01 CA196278, R01 CA160495]
- Department of Defense [W81XWH-18-1-0224]
- American Cancer Society-CEOs Against Cancer-PA Chapter Postdoctoral Fellowship [PF-18-096-01-LIB]
- NIH/NCI Cancer Center support grant [P30 CA056036]
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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.
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