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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通过米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 疗效


胰腺导管腺癌 （PDAC） 的生存率为 12%，多项针对 PDAC 的抗 PD-1 疗法测试的临床试验均失败，这表明需要一种新的治疗策略。在这项研究中，我们评估了抗寄生虫化合物米尔贝霉素肟 （MBO） 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抑制 PDAC 肿瘤生长分别降低了 49% 和 56%。此外，与对照组相比，MBO 治疗显着使荷瘤小鼠的存活率提高了 27 天。有趣的是，来自 MBO 治疗小鼠的肿瘤增加了 CD8 T 细胞的浸润。值得注意的是，CD8 T 细胞的耗竭显著降低了 MBO 在小鼠中的抗肿瘤功效。此外，MBO 显着增强了抗 PD-1 治疗的疗效，联合治疗导致肿瘤微环境中活性细胞毒性 T 细胞的比例增加。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。总体而言，我们的研究为使用 MBO 对抗 PDAC 提供了新的方向，并强调了重新利用 MBO 增强抗 PD-1 免疫治疗的潜力。