It is widely accepted that the immune system can exert either positive or negative influences on tumor growth. In many instances, tumors create an immunosuppressive microenvironment which contributes to tumor escape from immune destruction, particularly in pancreatic ductal adenocarcinoma (PDA). We have previously demonstrated that CD40 agonists can alter the tumor microenvironment and trigger a macrophage-dependent destruction of PDA in both humans and genetically engineered mice. Moreover, using a novel genetic lineage-tracing methodology, we now have preliminary data that invasive behavior and other elements of the metastatic cascade occur at the earliest stages of disease and are critically regulated by inflammation. Thus, we hypothesize that targeting immunosuppressive mechanisms in PDA will provide novel approaches to therapy for this otherwise treatment-resistant disease. In particular, we hypothesize that CD40 activation can re-educate both macrophages and T cells to trigger regression of a primary PDA tumor and impede metastatic spread in concert with other elements of the immune system. Our ultimate goal is to devise new therapies for PDA based on an understanding of immune regulatory networks in the tumor microenvironment. This proposal uses the multi-PI mechanism and will incorporate both mouse models and human patients. Specific Aims are to: (1) Understand the immunological mechanism(s) underlying the anti-tumor effect of agonist CD40 mAb, (2) Understand how inflammation and CD40 activation influence the metastatic cascade, 3) Determine the clinical and immunological impact of CD40 mAb in a clinical trial of patients with resectable pancreatic carcinoma.