Ovarian cancer is the leading cause of gynecologic cancer-related deaths and novel therapeutic strategies are required. Programmed cell death 1 and programmed cell death ligand 1 (PD-L1), which are key mediators of host immune tolerance, are associated with ovarian cancer progression. Recent evidence indicates the importance of IFNγ-induced PD-L1 for immune tolerance in ovarian cancer. This study aimed to reveal the therapeutic potential of suppressor of cytokine signaling 1 (SOCS-1), an endogenous inhibitor of the Janus kinase (JAK)–STAT signaling pathway, for the treatment of ovarian cancer. IHC assessment revealed that patients with ovarian cancer with high intratumoral STAT1 activation exhibited poor prognosis compared with patients with low STAT1 activation (P < 0.05). Stimulation of OVISE, OVTOKO, OV2944-HM-1 (HM-1), and CT26 cell lines with IFNγ induced STAT1 phosphorylation and PD-L1 expression. Adenovirus-mediated SOCS-1 gene delivery (AdSOCS-1) in HM-1 and CT26 cells in vitro potently inhibited IFNγ-induced STAT1 phosphorylation and PD-L1 upregulation, similar to the addition of JAK inhibitor I, but failed to inhibit their proliferation. Notably, intratumoral injection of AdSOCS-1, but not AdLacZ, significantly inhibited the tumor growth of HM-1 and CT26 cells subcutaneously transplanted in immunocompetent syngeneic mice. AdSOCS-1 reduced PD-L1 expression on tumors and restored the activation of tumor-infiltrating CD8+ T cells. Moreover, the antitumor effect of AdSOCS-1 was significantly attenuated by PD-L1 Fc-fusion protein administration in vivo, suggesting that the effect of AdSOCS-1 is mainly attributable to enhancement of tumor immunity. This study highlights the potential clinical utility of SOCS-1 as an immune checkpoint inhibitor. Mol Cancer Ther; 17(9); 1941–50. ©2018 AACR.

中文翻译：

---

携带 SOCS-1 基因的腺病毒载体的瘤内递送通过抑制 PD-L1 增强 T 细胞介导的抗肿瘤免疫

卵巢癌是妇科癌症相关死亡的主要原因，需要新的治疗策略。程序性细胞死亡 1 和程序性细胞死亡配体 1 (PD-L1) 是宿主免疫耐受的关键介质，与卵巢癌进展相关。最近的证据表明 IFNγ 诱导的 PD-L1 对卵巢癌免疫耐受的重要性。本研究旨在揭示细胞因子信号抑制因子 1 (SOCS-1)（一种 Janus 激酶 (JAK)-STAT 信号通路的内源性抑制剂）用于治疗卵巢癌的治疗潜力。IHC 评估显示，与低 STAT1 激活的患者相比，肿瘤内 STAT1 高激活的卵巢癌患者预后较差（P < 0.05）。OVISE、OVTOKO、OV2944-HM-1 (HM-1) 的刺激，IFNγ 和 CT26 细胞系诱导 STAT1 磷酸化和 PD-L1 表达。HM-1 和 CT26 细胞中腺病毒介导的 SOCS-1 基因传递 (AdSOCS-1) 可有效抑制 IFNγ 诱导的 STAT1 磷酸化和 PD-L1 上调，类似于添加 JAK 抑制剂 I，但未能抑制其增殖. 值得注意的是，肿瘤内注射 AdSOCS-1 而不是 AdLacZ，显着抑制皮下移植到免疫活性同基因小鼠中的 HM-1 和 CT26 细胞的肿瘤生长。AdSOCS-1 降低了肿瘤上 PD-L1 的表达，并恢复了肿瘤浸润性 CD8+ T 细胞的激活。此外，在体内 PD-L1 Fc 融合蛋白给药显着减弱了 AdSOCS-1 的抗肿瘤作用，表明 AdSOCS-1 的作用主要归因于增强肿瘤免疫。这项研究强调了 SOCS-1 作为免疫检查点抑制剂的潜在临床效用。摩尔癌症治疗; 17(9); 1941-50。©2018 AACR。