Inhibiting tumor necrosis factor-alpha diminishes desmoplasia and inflammation to overcome chemoresistance in pancreatic ductal adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common cancer death reasons. Anti-tumor necrosis factor-alpha (TNF-alpha) antibodies have shown promising effects in PDAC pre-clinical models. However, the prognostic values of TNF-alpha, underlying mechanisms by which anti-TNF-alpha treatments inhibit PDAC, and potential synergistic effects of anti-TNF-alpha treatments with chemotherapy are still unclear. Results and Methods: To identify the targeting values of TNF-alpha in PDAC, we measured TNF-alpha expression in different stages of PDAC initiation and evaluated its prognostic significance in a pancreatic cancer cohort. We found that TNF-alpha expression elevated in PDAC initiation process, and high expression of TNF-alpha was an independent prognostic marker of poor survival. We further evaluated anti-tumor effects of anti-TNF-alpha treatments in PDAC. Anti-TNF-alpha treatments resulted in decreased cell viability in both PDAC tumor cells and pancreatic satellite cells in similar dose in vitro. In vivo, anti-TNF-alpha treatments showed effects in reducing desmoplasia and the tumor promoting inflammatory microenvironment in PDAC. Combination of anti-TNF-alpha treatments with chemotherapy partly overcame chemoresistance of PDAC tumor cells and prolonged the survival of PDAC mouse model. Conclusions: In conclusion, our findings indicated that TNF-alpha in PDAC can be a prognostic and therapeutic target. Inhibition of TNF-alpha synergized with chemotherapy in PDAC resulted in better pre-clinical responses via killing tumor cells as well as diminishing desmoplasia and inflammation in PDAC tumor stroma.