Abstract Immune therapy has shown great promise in the treatment of a number of malignancies, but has not proven fruitful in fighting pancreatic ductal adenocarcinoma (PDA) using current modalities. One possible reason for this is the unique biology of the pancreatic cancer in establishing an immune suppressive microenvironment. We find that cross communication between cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs) and tumor cells is critical. Using animal models of PDA, we find that tumor cells polarize macrophages to TAMs both by activating CAFs to produce IL6 and by producing specific metabolites. TAMs then both suppress the immune response by arginine depletion by making Arginase 1 and by producing EGFR ligands, primarily HBEGF, to stimulate pancreatic cancer cells to express PDL1, an immune checkpoint ligand. We propose to use a combination of matched humanized patient derived xenografts (PDXs), organoid culture systems made up of cancer cells, immune cells and CAFs (ie “microtumors”) and a unique dual recombinase genetically engineered mouse model of PDA to test the hypothesis that treatment of tumors with inhibitors of STAT3, HBEGF, ARG1 or MEK will effectively synergize with PD1 inhibition, overcoming the powerful immune suppression created by the pancreatic cancer microenvironment.