The next-generation BET inhibitor, PLX51107, delays melanoma growth in a CD8-mediated manner
The next-generation BET inhibitor, PLX51107, delays melanoma growth in a CD8-mediated manner
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DOI：
10.1111/pcmr.12788
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发表时间：
2019-09-01
影响因子：
4.3
通讯作者：
Aplin, Andrew E.
中科院分区：
文献类型：
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作者：
Erkes, Dan A.;Field, Conroy O.;Aplin, Andrew E.
布罗莫结构域和末端外区域抑制剂（BETi）等表观遗传学药物通过肿瘤内在改变减缓肿瘤生长;然而，它们对抗肿瘤免疫的影响仍不清楚。最近的进展是下一代BETi的开发，它是有效的，并显示出良好的半衰期。在这里，我们测试了BETi PLX 51107对BRAF V600 E黑色素瘤同基因模型中肿瘤生长的基于免疫的影响。PLX 51107延迟黑色素瘤肿瘤生长，并增加肿瘤中活化、增殖和功能性CD 8 + T细胞，导致CD 8 + T细胞介导的肿瘤生长延迟。PLX 51107降低了肿瘤微环境中Cox 2的表达，增加了树突状细胞，并降低了PD-L1、FasL和IDO-1的表达。重要的是，PLX 51107延迟了抗PD-1治疗进展的肿瘤生长;这一反应与Cox 2水平降低、非免疫细胞上PD-L1表达降低和肿瘤内CD 8 + T细胞增加相关。因此，下一代BETi通过至少部分地对抗肿瘤CD 8 + T细胞产生作用，代表了转移性黑色素瘤的潜在一线和二级治疗策略。
Epigenetic agents such as bromodomain and extra-terminal region inhibitors (BETi) slow tumor growth via tumor intrinsic alterations; however, their effects on antitumor immunity remain unclear. A recent advance is the development of next-generation BETi that are potent and display a favorable half-life. Here, we tested the BETi, PLX51107, for immune-based effects on tumor growth in BRAF V600E melanoma syngeneic models. PLX51107 delayed melanoma tumor growth and increased activated, proliferating, and functional CD8+ T cells in tumors leading to CD8+ T-cell-mediated tumor growth delay. PLX51107 decreased Cox2 expression, increased dendritic cells, and lowered PD-L1, FasL, and IDO-1 expression in the tumor micro-environment. Importantly, PLX51107 delayed the growth of tumors that progressed on anti-PD-1 therapy; a response associated with decreased Cox2 levels, decreased PD-L1 expression on non-immune cells, and increased intratumoral CD8+ T cells. Thus, next-generation BETi represent a potential first-line and secondary treatment strategy for metastatic melanoma by eliciting effects, at least in part, on antitumor CD8+ T cells.