Dysregulation of regulatory B cells (Bregs), a type of immunosuppressive lymphocyte, are associated with development of autoimmune diseases and cancers. Bregs produce immune tolerance-inducing cell surface molecules and tolerogenic cytokines (interleukin [IL]-10 and transforming growth factor-beta). We previously showed that levels of the inflammatory cytokine IL-18 were increased in patients with pancreatic cancer. In the present study study, we found that pancreatic cancer cell-derived IL-18 increases Breg-induced immunosuppression. IL-18 also promoted B-cell proliferation and IL-10 expression in vivo and in vitro. In addition, IL-18 upregulated membrane PD-1 in B cells and inhibited the antibody-dependent cellular cytotoxicity of Tc cells and natural killer cells. Finally, the combination of a natural IL-18 inhibitor (IL-18BP) and a PD-1/PD-L1 inhibitor suppressed tumor growth and metastasis in a murine pancreatic cancer model. Our results show that IL-18 and PD-1/PD-L1 could be therapeutic targets in pancreatic cancer.