Niraparib plays synergistic antitumor effects with NRT in a mouse ovarian cancer model with HRP

IF 5 2区医学 Q2 Medicine Translational Oncology Pub Date : 2024-08-19 DOI:10.1016/j.tranon.2024.102094

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Abstract

Objective

PARPi offers less clinical benefit for HRP patients compared to HRD patients. PARPi has an immunomodulatory function. NRT therapy targets tumor neoantigens without off-target immune toxicity. We explored the synergy between Niraparib and NRT in enhancing antitumor activity in an HRP ovarian cancer mouse model.

Methods

In the C57BL/6 mouse ID8 ovarian cancer model, the effect of Niraparib on reshaping TIME was evaluated by immune cell infiltration analysis of transcriptomic data. The antitumor effects of Niraparib, NRT, and their combined use were systematically evaluated. To corroborate alterations in TILs, TAMs, and chemokine profiles within the TIME, we employed immunofluorescence imaging and transcriptome sequencing analysis.

Results

Niraparib increased the M1-TAMs and activated CD8+ T cells in tumor tissues of C57BL/6 mice with ID8 ovarian cancer. GSEA showed that gene set associated with immature DC and INFα, cytokines and chemokines were significantly enriched in immune feature, KEGG and GO gene sets, meanwhile CCL5, CXCL9 and CXCL10 play dominant roles together. In the animal trials, combined group had a tumor growth delay compared with Niraparib group (P < 0.01) and control group (P < 0.001), and longer survival compared with the single agent group (P<0.01) .

Conclusions

Niraparib could exert immune-reshaping effects, then acts synergistic antitumor effects with NRT in HRP ovarian cancer model. Our findings provide new ideas and rationale for combined immunotherapy in HRP ovarian cancer.

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尼拉帕利与 NRT 在小鼠卵巢癌 HRP 模型中发挥协同抗肿瘤作用

目的 PARPi 对 HRP 患者的临床疗效低于对 HRD 患者的疗效。PARPi 具有免疫调节功能。NRT 疗法针对肿瘤新抗原，不会产生脱靶免疫毒性。我们探讨了尼拉帕利和 NRT 在 HRP 卵巢癌小鼠模型中增强抗肿瘤活性的协同作用。方法在 C57BL/6 小鼠 ID8 卵巢癌模型中，通过转录组数据的免疫细胞浸润分析评估尼拉帕利对重塑 TIME 的影响。对尼拉帕利、NRT及其联合使用的抗肿瘤效果进行了系统评估。为了证实 TILs、TAMs 和趋化因子在 TIME 中的变化，我们采用了免疫荧光成像和转录组测序分析。GSEA显示，与未成熟DC和INFα相关的基因组、细胞因子和趋化因子在免疫特征、KEGG和GO基因组中显著富集，其中CCL5、CXCL9和CXCL10共同发挥主导作用。在动物实验中，联合用药组与尼拉帕利组（P <0.01）和对照组（P <0.001）相比肿瘤生长延迟，与单药组相比生存期延长（P <0.01）。我们的研究结果为HRP卵巢癌的联合免疫疗法提供了新的思路和依据。

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.