Loss of HRD functional phenotype impedes immunotherapy and can be reversed by HDAC inhibitor in ovarian cancer.
Loss of HRD functional phenotype impedes immunotherapy and can be reversed by HDAC inhibitor in ovarian cancer.
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DOI：
10.7150/ijbs.79654
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发表时间：
2023
影响因子：
9.2
通讯作者：
Zhu XF
中科院分区：
文献类型：
--
作者：
Yang D;Huang FX;Wei W;Li QQ;Wu JW;Huang Y;Li ZL;Zhang HL;Li X;Yuan QE;Chen QS;Feng GK;Rong D;Li JD;Zhu XF
近年来，同源重组缺陷（HRD）在卵巢癌免疫治疗疗效方面并未达到预期的实质性提升。本研究旨在探讨 HRD 功能表型作为强大的生物标志物在识别可能受益于免疫治疗的 HRD 患者中的作用。 HRD功能表型，即HRD-EXCUTE，被定义为HRD卵巢癌中上调的15个枢纽基因的平均水平。绘制决策树来评估 HRD-EXCUTE 在 HRD 患者中的关键作用。诱导 HRD-EXCUTE 的代理由 CMAP 网络（连接图）识别。在体外和体内检查了 PARPi 和 HDACi 促进 HRD-EXCUTE 的机制和免疫治疗作用。基于 HRD 和 HRD-EXCUTE 绘制的决策树表明，不具有 HRD 功能表型的 HRD 患者对免疫治疗基本上没有反应，这一点得到了免疫治疗队列的验证。此外，HRD 患者中 HRD-EXCUTE 的缺失减弱了免疫原性并抑制了肿瘤微环境中的免疫细胞。此外，Niraparib 与 Entinostat 联合通过激活 cGAS-STING 通路并增加组蛋白乙酰化来诱导 HRD-EXCUTE。联合治疗可以增强免疫细胞的细胞毒性，促进前免疫细胞浸润到腹水中，从而抑制卵巢癌的生长。 HRD 功能表型 HRD-EXCUTE 被设置为一种有效的生物标志物，用于确定 HRD 患者是否可以从免疫治疗中受益。 HRD 患者中 HRD-EXCUTE 的丧失很大程度上对免疫治疗不敏感。 PARPi 与 HDACi 的组合可以通过增强 HRD 功能表型来提高基于 PARPi 的免疫疗法对卵巢癌的疗效。
In recent years, homologous recombination deficiency (HRD) has not achieved the expected substantial promotion of immunotherapeutic efficacy in ovarian cancer. This study aims to explore the role of HRD functional phenotype as a powerful biomarker in identifying HRD patients who may benefit from immunotherapy. HRD functional phenotype, namely HRD-EXCUTE, was defined as the average level of the 15 hub genes upregulated in HRD ovarian cancer. A decision tree was plotted to evaluate the critical role of HRD-EXCUTE in HRD patients. Agents inducing HRD-EXCUTE were identified by CMAP web (Connectivity Map). The mechanisms and immunotherapeutic effect of PARPi and HDACi in promoting HRD-EXCUTE was examined in vitro and in vivo. The decision tree plotted on the basis of HRD and HRD-EXCUTE indicated the HRD patients without the HRD functional phenotype were largely unresponsive to immunotherapy, which was validated by the immunotherapeutic cohorts. Furthermore, loss of HRD-EXCUTE in the HRD patients attenuated immunogenicity and inhibited immune cells in tumor microenvironment. Moreover, Niraparib combined with Entinostat induced HRD-EXCUTE by activating the cGAS-STING pathway and increasing the histone acetylation. The combination therapy could enhance the cytotoxicity of immune cells, and promote pro-immune cells infiltrating into ascites, resulting in inhibited ovarian cancer growth. The HRD functional phenotype HRD-EXCUTE was set up as a potent biomarker to identify whether HRD patients can benefit from immunotherapy. Loss of HRD-EXCUTE in HRD patients were largely insensitive to immunotherapy. The combination of PARPi with HDACi could improve the efficacy of the PARPi-based immunotherapy in ovarian cancer by augmenting the HRD functional phenotype.
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影响因子：
16.6
作者：
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通讯作者：
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影响因子：
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影响因子：
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10.3
作者：
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通讯作者：
Jeyasekharan, Anand D.