Immune therapies in pancreatic ductal adenocarcinoma: Where are we now?

Figure 2 Summary of the mechanisms responsible for pancreatic ductal adenocarcinoma resistance to immune therapy. The circle outlines the three steps of the cancer-immunity cycle: (1) Immunogenicity (yellow); (2) T-cell recruitment and (3) activation. Pancreatic ductal adenocarcinoma resistance to immune therapy is due to the combination of several factors: (1) Low tumor immunogenicity, with a low mutation rate and low neaoantigen burden compared to other tumors (e.g., melanoma); (2) low T-cell recruitment and (3) activation: the dense desmoplastic stroma generates high interstitial pressure; this results in poor tumor perfusion and intra-tumor hypoxia, which in turn activates fibroblasts to release immunosuppressive cytokines (e.g., TGFβ, IL-6, CSF1 = “chemical barrier”) that lead to the recruitment of immunosuppressive cells (M2 macrophages, TREG, MDSC) and exclusion and anergy of effector T cells. CSF1: Colony stimulating factor 1; IL-6: Interleukin-6; MDSC: Myeloid-derived suppressive cells; TGFβ: Transforming growth factor β; TREG: T regulatory cells.