Pancreatic ductal adenocarcinoma (PDAC) has a survival rate of 12%, and multiple clinical trials testing anti-PD-1 therapies against PDAC have failed, suggesting a need for a novel therapeutic strategy. In this study, we evaluated the potential of milbemycin oxime (MBO), an antiparasitic compound, as an immunomodulatory agent in PDAC. Our results show that MBO inhibited the growth of multiple PDAC cell lines by inducing apoptosis. studies showed that the oral administration of 5 mg/kg MBO inhibited PDAC tumor growth in both subcutaneous and orthotopic models by 49% and 56%, respectively. Additionally, MBO treatment significantly increased the survival of tumor-bearing mice by 27 days as compared to the control group. Interestingly, tumors from MBO-treated mice had increased infiltration of CD8 T cells. Notably, depletion of CD8 T cells significantly reduced the anti-tumor efficacy of MBO in mice. Furthermore, MBO significantly augmented the efficacy of anti-PD-1 therapy, and the combination treatment resulted in a greater proportion of active cytotoxic T cells within the tumor microenvironment. MBO was safe and well tolerated in all our preclinical toxicological studies. Overall, our study provides a new direction for the use of MBO against PDAC and highlights the potential of repurposing MBO for enhancing anti-PD-1 immunotherapy.

中文翻译：

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米尔贝霉素肟重编程肿瘤免疫微环境可抑制胰腺肿瘤生长并增强抗 PD-1 功效


胰腺导管腺癌 (PDAC) 的生存率为 12%，并且针对 PDAC 测试抗 PD-1 疗法的多项临床试验都失败了，这表明需要一种新的治疗策略。在这项研究中，我们评估了米尔倍霉素肟 (MBO)（一种抗寄生虫化合物）作为 PDAC 免疫调节剂的潜力。我们的结果表明，MBO 通过诱导细胞凋亡来抑制多种 PDAC 细胞系的生长。研究表明，口服 5 mg/kg MBO 在皮下和原位模型中分别抑制 PDAC 肿瘤生长 49% 和 56%。此外，与对照组相比，MBO 治疗显着延长了荷瘤小鼠的生存期 27 天。有趣的是，MBO 治疗小鼠的肿瘤中 CD8 T 细胞的浸润增加。值得注意的是，CD8 T 细胞的耗竭显着降低了 MBO 在小鼠中的抗肿瘤功效。此外，MBO 显着增强了抗 PD-1 疗法的疗效，并且联合治疗导致肿瘤微环境中活性细胞毒性 T 细胞的比例更高。在我们所有的临床前毒理学研究中，MBO 都是安全且耐受性良好的。总的来说，我们的研究为使用 MBO 对抗 PDAC 提供了一个新方向，并强调了重新利用 MBO 来增强抗 PD-1 免疫治疗的潜力。