Heme Oxygenase-1 Inhibition Potentiates the Effects of Nab-Paclitaxel-Gemcitabine and Modulates the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies. Chemotherapy has had limited success in extending the life span of patients with advanced PDAC. Thus, new treatment approaches are needed. Heme oxygenase-1 (HO-1) is a key enzyme for the protection of cells against oxidative stress. Interestingly, HO-1 is overexpressed in several cancers, including PDAC. In the present study, our findings demonstrate the novel role of HO-1 in vivo in PDAC progression and in sensitizing tumor cells to cytotoxic chemotherapy by modulating the tumor microenvironment (TME). ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Tumor hypoxia plays an active role in promoting tumor progression, malignancy, and resistance to therapy in PDAC. We present evidence that nab-paclitaxel–gemcitabine (NPG) and/or a hypoxic tumor microenvironment (TME) up-regulate heme oxygenase-1 (HO-1), providing a survival advantage for tumors. Using PDAC cells in vitro and a PDAC mouse model, we found that NPG chemotherapy up-regulated expression of HO-1 in PDAC cells and increased its nuclear translocation. Inhibition of HO-1 with ZnPP and SnPP sensitized PDAC cells to NPG-induced cytotoxicity (p < 0.05) and increased apoptosis (p < 0.05). Additionally, HO-1 expression was increased in gemcitabine-resistant PDAC cells (p < 0.05), and HO-1 inhibition increased GEM-resistant PDAC sensitivity to NPG (p < 0.05). NPG combined with HO-1 inhibitor inhibited tumor size in an orthotopic model. In parallel, HO-1 inhibition abrogated the influx of macrophages and FoxP3+ cells, while increasing the proportion of CD8+ infiltration in the pancreatic tumors. These effects were mediated primarily by reducing expression of the immunosuppressive cytokine IL-10.