Lu Jiefang, Liu Haiying, Wang Binming, Chen Chengcheng, Bai Fumao, Su Xiaoping, Duan Ping
Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, China; Department of Obstetrics and Gynecology, Lishui People's Hospital, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital of Lishui College, China.
Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, China; Department of Obstetrics and Gynecology, Lishui People's Hospital, China.
Transl Oncol. 2024 Nov;49:102094. doi: 10.1016/j.tranon.2024.102094. Epub 2024 Aug 19.
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.
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.
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) .
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.
与同源重组缺陷（HRD）患者相比，聚（A）特异性核糖核酸酶抑制剂（PARPi）对同源重组 proficient（HRP）患者的临床益处较小。PARPi具有免疫调节功能。新抗原受体靶向疗法（NRT）靶向肿瘤新抗原且无脱靶免疫毒性。我们在HRP卵巢癌小鼠模型中探索了尼拉帕利与NRT在增强抗肿瘤活性方面的协同作用。
在C57BL/6小鼠ID8卵巢癌模型中，通过对转录组数据进行免疫细胞浸润分析，评估尼拉帕利对重塑肿瘤免疫微环境（TIME）的影响。系统评估了尼拉帕利、NRT及其联合使用的抗肿瘤作用。为了证实TIME内肿瘤浸润淋巴细胞（TILs）、肿瘤相关巨噬细胞（TAMs）和趋化因子谱的变化，我们采用了免疫荧光成像和转录组测序分析。
尼拉帕利增加了C57BL/6小鼠ID8卵巢癌肿瘤组织中的M1-TAMs并激活了CD8+T细胞。基因集富集分析（GSEA）表明，与未成熟树突状细胞和INFα、细胞因子和趋化因子相关的基因集在免疫特征、京都基因与基因组百科全书（KEGG）和基因本体（GO）基因集中显著富集，同时趋化因子配体5（CCL5）、趋化因子CXC配体9（CXCL9）和趋化因子CXC配体10（CXCL10）共同发挥主导作用。在动物试验中，联合治疗组与尼拉帕利组相比肿瘤生长延迟（P<0.01），与对照组相比（P<0.001），且与单药组相比生存期更长（P<0.01）。
尼拉帕利可发挥免疫重塑作用，然后在HRP卵巢癌模型中与NRT发挥协同抗肿瘤作用。我们的研究结果为HRP卵巢癌的联合免疫治疗提供了新的思路和理论依据。
