Oncolytic HSV Therapy Modulates Vesicular Trafficking Inducing Cisplatin Sensitivity and Antitumor Immunity.
Oncolytic HSV Therapy Modulates Vesicular Trafficking Inducing Cisplatin Sensitivity and Antitumor Immunity.
复制标题
DOI：
10.1158/1078-0432.ccr-20-2210
复制
发表时间：
2021-01-15
期刊：
影响因子：
--
通讯作者：
Kaur B
中科院分区：
文献类型：
--
作者：
Hong B;Chapa V;Saini U;Modgil P;Cohn DE;He G;Siddik ZH;Sood AK;Yan Y;Selvendiran K;Pei G;Zhao Z;Yoo JY;Kaur B
在这里，我们研究了溶瘤单纯疱疹病毒(OHSV)治疗对顺铂耐药卵巢癌(OC)顺铂敏感性的影响，以及联合应用对免疫治疗的影响。在对铂耐药的人和小鼠OC腹膜转移模型(n=9-10/组)中，评估了联合治疗的疗效。用RNA测序和流式细胞术检测治疗组小鼠脾细胞的抗肿瘤免疫应答(n=3/组)。用抗PD-1抗体评价对体内检查点抑制的影响。基因本体论途径分析发现，感染细胞中细胞外小泡(EV)相关途径被破坏(FDR=2.97E-57)。从机制上讲，我们发现EV上表达的转运蛋白表达减少与CP外流有关。顺铂滞留增加导致顺铂-DNA加合物增加，从而导致微核和cGAS-STING通路的激活，从而显著激活天然免疫细胞，从而提高抗肿瘤免疫能力和疗效。在携带铂耐药OC的小鼠中，我们还观察到PD-L1对肿瘤细胞的反馈诱导，这使联合治疗的小鼠对抗PD-1免疫检查点治疗增敏。据我们所知，这是第一个显示HSV诱导的顺铂在感染细胞中滞留的报告。随之而来的损伤DNA以微核的形式从细胞中排出，导致炎症反应的诱导和抗肿瘤免疫的教育。联合治疗还创造了一个环境，使肿瘤对免疫检查点治疗敏感。
Here we investigated the impact of oncolytic HSV (oHSV) treatment on cisplatin sensitivity of platin resistant ovarian cancer (OC), and the impact of the combination on immunotherapy. Therapeutic efficacy of the combination was assessed in platin resistant human and murine OC peritoneal metastatic mouse models (n=9–10/group). RNA sequencing along with flow cytometry of splenocytes from treated mice was employed to examine the effect of anti-tumor immune response (n=3/group). Anti-PD-1 antibody was performed to evaluate impact on checkpoint inhibition in vivo. Gene ontology pathway analysis uncovered disruption of cellular extracellular vesicle (EV) related pathways in infected cells (FDR=2.97E-57). Mechanistically we identified reduced expression of transporters expressed on EV implicated in CP efflux. The increased cisplatin retention led to increased cisplatin-DNA adducts, which resulted in micronuclei and the subsequent activation of cGAS-STING pathway with a significant activation of innate immune cells and translated to an increase in anti-tumor immunity and efficacy. In mice bearing platin resistant OC we also observed a feed-back induction of PD-L1 on tumor cells, which sensitized combination treated mice to anti-PD-1 immune checkpoint therapy. To our knowledge this is the first report to show HSV induced cisplatin retention in infected cells. The consequential increased damaged DNA was then expelled from cells as micronuclei which resulted in induction of inflammatory responses and education of anti-tumor immunity. The combination therapy also created an environment that sensitized tumors to immune checkpoint therapy.