文章目录

靶向免疫抑制巨噬细胞克服brca1相关三阴性乳腺癌中PARP抑制剂的耐药

原文发布日期：2020-12-14

英文摘要：

摘要翻译：

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文章：

靶向免疫抑制巨噬细胞克服brca1相关三阴性乳腺癌中PARP抑制剂的耐药

Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer

原文发布日期：2020-12-14

英文摘要：

Despite objective responses to poly(ADP-ribose) polymerase (PARP) inhibition and improvements in progression-free survival (PFS) compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high-dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in breast cancer susceptibility (BRCA)-associated TNBC. Through multi-omics profiling, we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming, driven by the sterol regulatory element-binding protein 1 (SREBF1, SREBP1) pathway. Combining PARP inhibitor therapy with colony-stimulating factor 1 receptor (CSF1R)-blocking antibodies significantly enhanced innate and adaptive antitumor immunity and extended survival in mice with BRCA-deficient tumors in vivo, and this was mediated by CD8+ T cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate that combined PARP inhibition and macrophage-targeting therapy induces a durable reprogramming of the tumor microenvironment (TME), thus constituting a promising therapeutic strategy for TNBC.

摘要翻译：

尽管聚（辅基团磷酸二酯酶）PARP抑制剂对BRCA相关三阴性乳腺癌（TNBC）患者的客观应答以及疾病进展无病生存期（PFS）的改善与标准化疗相比具有优势，但这些好处是暂时性的。通过人类TNBC的大分子单细胞分析，我们在这里证明了，在BRCA相关TNBC中，巨噬细胞是最主要侵袭性免疫细胞类型。通过多组学分析，我们显示PARP抑制剂通过葡萄糖和脂质代谢的重新编程增强了巨噬细胞的抗肿瘤和促肿瘤特性，这些特性部分依赖于SREBP1/SREBR1途径驱动。将PARP抑制剂与CSF1R（成纤维细胞生长因子受体）抑制抗体联合使用在 vivo 中明显增强了小鼠体内BRCA缺陷肿瘤患者的固有免疫和适应性抗肿瘤免疫，并延长了生存期，这种作用部分由CD8+ T 细胞介导。综上所述，我们的结果揭示巨噬细胞介导的免疫抑制是PARP抑制剂治疗的一个弱点，并且组合使用PARP抑制剂和靶向巨噬细胞疗法诱导肿瘤微环境（TME）的持久改变，因此是一种有前景的治疗方法。