The prognosis of pancreatic ductal carcinoma (PDAC) remains dismal, with an overall 5-year survival rate of 7%. Immunotherapy (IT) has provided new hope for other hard-to-treat cancers, but PDAC has shown striking resistance to IT by orchestrating mechanisms of immune escape. This spurs an interest to identify novel strategies to improve PDAC sensitivity to IT. We recently unveiled that perturbating redox homeostasis by targeting the antioxidant protein peroxiredoxin 4 (PRDX4) render pancreatic cancer cells highly vulnerable. PRDX4 supports redox homeostasis by metabolizing H2O2 in the endoplasmic reticulum (ER), and its loss leads to oxidative stress and toxicity. Interestingly, cell death induced by PRDX4 depletion is accompanied by DNA damage and accumulation of cytosolic DNA, a potent primer for immune therapy. In line with that, PRDX4 knockdown results in the transcriptional upregulation of inflammatory genes, including type I interferons (IFNs), primary cytokines and interferon-stimulated genes (ISGs). Importantly, our data indicate that this induction is dependent on the critical regulator of the innate immune responses, STING, as treatment with a STING inhibitor, or a STING knockdown, substantially blunts their upregulation. It is known that following DNA damage detection, the ER-localized STING translocates to the Golgi, where it associates with the kinase TBK1 and mediates the induction of inflammatory target genes, depending on IRF3 and NF-κB transcription factors. We observe an activation of downstream STING effectors upon PRDX4 loss, and co-depletion with NFκB significantly rescues the upregulation of those genes. As such, we propose that PRDX4 links ER-specific redox vulnerability to innate immunity signaling in PDAC. Since PRDX4 loss causes increased DNA damage and inflammatory signaling, our preliminary data suggest that PRDX4 could be a novel therapeutic target that may act synergistically with immune checkpoint inhibitors.

Citation Format: Lucie Malbeteau, Pallavi Jain, Shane Harding, Bradley Wouters, Marianne Koritzinsky. PRDX4 links ER-specific redox vulnerability to innate immunity in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 124.