Abstract A102: Targeting serpin B9 to improve pancreatic cancer immunochemotherapy

Serpin B9 (SPB9), a potent endogenous inhibitor of granzyme B (GrB), provides cytoprotective effects against self-inflicted injury caused by GrB in cytotoxic T cells. However, it has been established that SPB9 can protect tumor cells from GrB mediated destruction, whether GrB originates from cytotoxic lymphocytes or is self-produced by tumor cells. We showed that SPB9 was significantly induced by gemcitabine (GEM) or oxaliplatin (OXA) in pancreatic cancer cells in vitro and in vivo, suggesting that SPB9 may represent a new therapeutic target to improve pancreatic cancer immunochemotherapy. One limitation of systemic use of small molecule inhibitors of SPB9 is the undesired effects on T cells, and possibly other normal cells. We hypothesized that nanoparticles (NPs)-mediated selective delivery of SPB9 siRNA (siSPB9) to tumors cells may represent a safer and more effective approach to inhibit both basal and chemotherapy-induced SPB9. To this end, we have developed a siRNA nanocarrier that is based on GEM-conjugated polymer. Such strategy can protect GEM from cytidine deaminase-mediated degradation and achieve simultaneous codelivery of GEM and siSPB9. Importantly, the presence of GEM improves the stability of siRNA NPs through its interaction with siRNA via π–π stacking and hydrophobic interactions. Meanwhile, OXA was modified with oleic acid to be incorporated into the NPs to further facilitate combination therapy. GEM+OXA-coloaded NPs are small in size (< 100 nm) and close to neutral in surface charge. The NPs were stable and protected siRNA from nuclease-mediated degradation. Near infrared fluorescence (NIRF) whole body imaging of tumor-bearing mice and ex vivo imaging of excised tumors and other organs showed concentrated accumulation of Cy5.5 siRNA-labeled NPs at tumor tissues. Codelivery of siSPB9 and chemotherapy via the NPs led to drastic inhibition of tumor growth in a syngeneic subcutaneous (s.c.) KPC model. Studies are currently ongoing to further elucidate the underlying mechanism of improved treatment. Targeting SPB9 in combination with chemotherapy may represent a new promising therapy for pancreatic cancer, which warrants more studies in the future. Citation Format: Yiqing Mu, Haozhe Huang, Song Li. Targeting serpin B9 to improve pancreatic cancer immunochemotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A102.