Abstract 6153: Overcoming immunosuppression in pancreatic cancer: Efficacy of polyamine blockade and anti-PD-1 combinational therapy

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive cancer, with an only a 13% 5-year survival rate. This low survival rate is due to its dense microenvironment, late-stage diagnosis, and limited treatment options. Polyamines, small molecules essential for cell growth, play a critical role here because their dysregulation is linked to PDAC's tumor growth, invasion, and metastasis. Additionally, the tumor microenvironment becomes increasingly “cold,” or resistant to immune responses. This resistance is driven by the recruitment of immunosuppressive populations and immune evasion mechanisms, such as the programmed death-1 (PD-1) pathway, which conceals PDAC from immune detection. This study aims to explore the interaction between polyamines, the PDAC immune microenvironment, and evaluate the effectiveness of combining Polyamine Blockade Therapy (PBT) with anti-PD-1 inhibitors as a novel immunotherapy strategy. Using an orthotopic mouse model of PDAC with syngeneic GFP-Luc2 cells, we assessed the impact of PBT, consisting of Difluoromethylornithine (DFMO) and the polyamine transport inhibitor (PTI) Trimer 44NMe (Trimer PTI), in conjunction with anti-PD-1 therapy. Tumor growth was monitored by bioluminescence in vivo and shifts in immune populations were assessed using flow cytometry. The combination of simultaneous PBT and anti-PD-1 treatment resulted in a significant reduction in tumor mass, decreased levels of immunosuppressive cells, and an increase in anti-tumor immune populations. The combination of Polyamine Blockade Therapy with anti-PD-1 inhibition shows promise as an effective immunotherapy for PDAC, potentially improving patient outcomes by disrupting the polyamine-mediated immunosuppressive network while enhancing anti-tumor immunity. Citation Format: Joseph A. Goode, Diana Gaete-Alvarez, Otto Phanstiel, Deborah Altomare. Overcoming immunosuppression in pancreatic cancer: Efficacy of polyamine blockade and anti-PD-1 combinational therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6153.