194 Background: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immunosuppressive cells that are upregulated in cancer. Little is known about the prevalence and importance of MDSC in pancreas adenocarcinoma (PA). Here, we quantify MDSC prevalence in patients with PA and assess the efficacy of MDSC depletion in a murine model of PA. Methods: Peripheral blood and tumor samples were collected from patients with PA, analyzed for MDSC (CD15+11b+) by flow cytometry (FC) and compared to cancer-free controls (CFC). The suppressive capacity of MDSC and the effectiveness of MDSC depletion were assessed in C57BL/6 mice inoculated with Pan02, a murine PA, and treated with placebo or zoledronic acid (ZA), a potent aminobisphosphonate previously shown to target MDSC. Endpoints included tumor size, survival, and MDSC prevalence. Tumor cell infiltrate was analyzed by FC for MDSC (Gr1+CD11b+) and effector T cells; tumor cytokine levels were measured by Luminex assay. Results: Patients with PA demonstrated increased circulating MDSC compared to CFC, which correlated with disease stage (metastatic PA: 68%±3.6% of CD45+ cells, resectable PA: 57%±3.5%, CFC: 37%±3.6%; p<0.0001). Normal pancreas tissue showed no MDSC infiltrate while PA avidly recruited CD11b+15+ cells to the primary tumor. Murine tumors similarly recruited MDSC that actively suppressed CD8+ T cells in vitro measured by CFSE dilution and accelerated tumor growth in vivo by adoptive transfer with Pan02 cells (p<0.001). Treatment with ZA impaired MDSC accumulation in the tumor (Placebo: 78%, ZA: 51%, p<0.05) resulting in delayed tumor growth rate (p<0.0001) and prolonged median survival (Placebo: 59 days, ZA: 73 days, p<0.05). MDSC blockade increased recruitment of T cells to the tumor (CD4: 4.4%±1.1% vs 12.2%±2.0%, p<0.05; CD8: 3.9%±1.3% vs 10.6%±2.2%, p<0.05) and a more robust type 1 response with increased levels of IFN-g (p<0.05) and decreased levels of IL-10 (p<0.05). Conclusions: MDSC are an important mediator of tumor-induced immunosuppression in PA. Treatment with ZA effectively blocks MDSC accumulation improving anti-tumor response in animal studies. Efforts to block MDSC may represent a novel treatment strategy for PA. [Table: see text]