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.

中文翻译：

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PLX3397抑制黑色素瘤中肿瘤内巨噬细胞的积累，并改善溴结构域和末端外抑制剂的功效。

Bromodomain和末端外抑制剂（BETi）部分地通过肿瘤细胞内在改变和抗肿瘤CD8 + T细胞反应的启动来延迟肿瘤的生长。相比之下，BETi对促肿瘤免疫反应的作用仍不清楚。在这里，我们显示了下一代BETi PLX51107在Braf V600E黑色素瘤同系小鼠模型中将肿瘤的生长延迟了不同程度。这些差异反应与BETi治疗期间肿瘤相关巨噬细胞的涌入有关。对PLX51107反应不良的肿瘤显示出大量的集落刺激因子1受体（CSF-1R）阳性肿瘤相关巨噬细胞大量涌入。我们用CSF-1R抑制剂PLX3397和PLX51107联合清除了CSF-1R +肿瘤相关的巨噬细胞。PLX3397的治疗增强了PLX51107在体内反应较差的Braf V600E同基因黑色素瘤中的功效。这些发现表明，肿瘤相关的巨噬细胞蓄积限制了BETi的功效，并且与PLX3397共同治疗可以改善对PLX51107的反应，为转移性黑色素瘤患者提供了一种潜在的新型联合疗法。