Autophagy Inhibition Reprograms the Tumor Microenvironment of Pancreatic Cancer to Promote Macrophage Phagocytosis of Tumor Cells.

UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) relies on elevated autophagy to support metabolism, proliferation, and immune evasion. Inhibiting autophagy has been reported to improve response rates in patients with PDAC. In this work, we identified a mechanism to explain how the loss of autophagy in PDAC triggers reprogramming of the tumor microenvironment (TME) to ultimately stimulate an antitumor response. Autophagy inhibition in PDAC recruited macrophages via the CXCL1/2-CXCR2 axis. Simultaneously, the loss of autophagy resulted in a decrease in the canonical "don't eat me" ligand CD47 on tumor cells, thereby inducing their susceptibility to macrophage phagocytosis. Although CD8+ T cells were critical to the antitumor immune response to autophagy inhibition in PDAC, they were not directly involved in cytotoxicity but played a critical role in stimulating macrophage phagocytosis of tumor cells. Taken together, this study strongly supports the implementation of autophagy inhibition in pancreatic cancer and highlights a crucial link between PDAC biology and the TME-macrophage cross-talk that effectively promotes tumor cell killing.

SIGNIFICANCE: Inhibition of autophagy in pancreatic cancer promotes antitumor immunity through a stepwise process of recruiting macrophages and enhancing phagocytosis of cancer cells, providing a potential therapeutic strategy for this deadly tumor type.