The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1-/- murine model of ovarian cancer
The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1-/- murine model of ovarian cancer
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DOI：
10.1016/j.bbrc.2015.05.083
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发表时间：
2015-08-07
影响因子：
3.1
通讯作者：
Goldberg, Michael S.
中科院分区：
文献类型：
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作者：
Huang, Jing;Wang, Lei;Goldberg, Michael S.
家族性乳腺癌和卵巢癌通常是由BRCAL的遗传突变引起的，而目前这类患者的预后相当差，抑制多adp核糖聚合酶1 （PARPI）可在同源重组缺陷的细胞中诱导合成致死。BMN 673是一种有效的PARP1抑制剂，正在临床评估用于治疗brca突变型癌症。利用brca1缺失小鼠上皮性卵巢癌细胞系BR5FVB1-Akt，我们研究了BMN 673的抗肿瘤作用是否超出其已知的促凋亡功能。给药适量的BMN 673可显著提高皮下或腹腔肿瘤小鼠的存活率。因此，我们推测BMN 673可能影响肿瘤微环境中免疫细胞的组成和功能。事实上，BMN 673显著增加了腹膜CD8(+) T细胞和NK细胞的数量，以及它们产生的ifn - γ和tnf - α。这些数据表明，BMN 673引起的细胞应激不仅可以诱导癌细胞的内在凋亡，还可以诱导癌细胞的外在抗肿瘤免疫作用。因此，BMN 673可能作为一种有希望的辅助治疗免疫治疗，在同源重组中肿瘤有缺陷的患者中实现持久的反应。(C) 2015爱思唯尔公司版权所有。
Familial breast and ovarian cancer are often caused by inherited mutations of BRCAL While current prognoses for such patients are rather poor, inhibition of poly-ADP ribose polymerase 1 (PARPI) induces synthetic lethality in cells that are defective in homologous recombination. BMN 673 is a potent PARP1 inhibitor that is being clinically evaluated for treatment of BRCA-mutant cancers. Using the Brca1-deficient murine epithelial ovarian cancer cell line BR5FVB1-Akt, we investigated whether the antitumor effects of BMN 673 extend beyond its known pro-apoptotic function. Administration of modest amounts of BMN 673 greatly improved the survival of mice bearing subcutaneous or intraperitoneal tumors. We thus hypothesized that BMN 673 may influence the composition and function of immune cells in the tumor microenvironment. Indeed, BMN 673 significantly increases the number of peritoneal CD8(+) T cells and NK cells as well as their production of IFN-gamma and TNF-alpha. These data suggest that the cell stress caused by BMN 673 induces not only cancer cell-intrinsic apoptosis but also cancer cell-extrinsic antitumor immune effects in a syngeneic murine model of ovarian cancer. BMN 673 may therefore serve as a promising adjuvant therapy to immunotherapy to achieve durable responses among patients whose tumors harbor defects in homologous recombination. (C) 2015 Elsevier Inc. All rights reserved.