Reprogramming tumor immune microenvironment by milbemycin oxime results in pancreatic tumor growth suppression and enhanced anti-PD-1 efficacy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a survival rate of 12% and multiple clinical trials testing anti-PD1 therapies against PDAC have failed suggesting a need of 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 growth of multiple PDAC cell lines by inducing apoptosis. In vivo studies showed that 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 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. Further, MBO significantly augmented the efficacy of anti-PD1 therapy, and the combination treatment resulted in a greater proportion of active cytotoxic T cells within the TME. 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-PD1 immunotherapy.