Inflammatory networks and T cell immunosurveillance in pancreatic cancer

Cancer-associated inflammation plays a decisive role in restraining anti-tumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA) for which a massive infiltration of immunosuppressive leukocytes into tumor stroma accompanies cancer growth. Gr-1+ CD11b+ cells, often called myeloid-derived suppressor cells (MDSCs), are a key feature of cancer-related inflammation in this disease, but the crosstalk between Gr-1+ CD11b+ cells and PDA tumor cells remains incompletely understood. Here, using a genetically engineered mouse model of invasive PDA, we show that Gr-1+ CD11b+ myeloid cells accumulate in primary and metastatic lesions, exhibit high levels of arginase and iNOS activity, and potently inhibit proliferation of antigen-specific T cells. Among the many cytokines and chemokines produced by PDA tumors, GM-CSF was both necessary and sufficient to drive proliferation and differentiation of c-kit + Gr-1neg CD11bneg splenocytes from tumor-bearing mice into functional MDSCs. in vivo, abrogation of GM-CSF accomplished either with neutralizing antibodies or shRNA inhibited the recruitment of Gr-1+ CD11b+ cells to the tumor microenvironment and blocked tumor development. This inhibition of tumor growth was reversed by in vivo CD8+ T cell depletion. Thus, our findings demonstrate that tumor-derived GM-CSF regulates a major component of myeloid inflammation and T cell immunity in PDA and suggest new targets with therapeutic potential for disrupting cancer inflammation and enhancing immunity. Many of these findings extend to other gastrointestinal cancers, such as oral and esophageal squamous cell carcinoma, which we evaluated using a genetically engineered mouse model driven by genetic lesions distinct from the pancreas model. We observed desmoplasia and a prominent myeloid inflammatory response around early and advanced lesions, and strikingly, tumor progression was significantly halted when this inflammation was eliminated. Collectively, these findings suggest a common theme among epithelial-derived upper gastrointestinal tumors by which tumor-derived factors drive an inflammatory program that fosters tumorigenesis and tumor invasion, at least in part through the inhibition of anti-tumor immunity