Abstract
Immune checkpoint inhibitors (ICIs) show limited success in treating pancreatic ductal adenocarcinoma (PDAC), largely due to immune evasion mechanisms, including downregulating expression of major histocompatibility complex class I (MHC-I). Our retrospective analysis demonstrated that smoking - a state of elevated CO exposure - is correlated with increased MHC I expression in pancreatic tumors. Here we tested our hypothesis that introducing exogenous CO augments the anti-cancer effects of immunotherapy. To evaluate this influence, we created a novel oral delivery system for CO, termed CO-Gas-entrapping materials (GeMs), utilizing Food and Drug Administration Generally Recognized as Safe components. In vitro studies demonstrated that CO exposure increased MHC-I and PD-L1 gene and protein expression in various pancreatic cancer cell lines, as well as enhancing T-cell migration and recruitment. In vivo studies showed increased T-cell infiltration in PDAC allograft tumors treated with the combination therapy as confirmed by flow cytometry and immunohistochemical analysis. Further, CO-GeMs combined with ICIs significantly suppressed tumor growth in multiple PDAC mouse models, including subcutaneous and hepatic metastatic allograft models. These findings suggest that CO enhances immune recognition to potentiate the efficacy of ICIs in PDAC. Thus, our CO-GeMs offer a safe, effective method for systemic CO delivery to treat cancer, representing a promising adjunct to immunotherapy in PDAC and potentially other malignancies.