Abstract 3288: Wildtype IDH1 blockade as a strategy to modulate the tumor microenvironment and boost immune responses in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a dense tumor stroma and a five-year survival rate of less than 13%. Its poor prognosis arises from rapid progression, early metastasis, and resistance to therapy. Despite, advancements in chemotherapy and immunotherapy, outcomes remain dismal, largely due to the immunosuppressive tumor microenvironment (TME). Previous work in our lab demonstrated the efficacy of ivosidenib, an FDA-approved inhibitor of mutant isocitrate dehydrogenase 1 (IDH1), also inhibits wild-type IDH1(wtIDH1) under conditions mimicking the PDAC TME. Here we show that targeting wtIDH1 suppresses cancer cell proliferation by inducing apoptosis, increasing reactive oxygen species (ROS) levels, and enhancing antitumor immune responses by reducing immunosuppressive immune cell populations. In vitro studies were conducted using Miapaca-2, Panc-1 and KPC cell lines. Cells were cultured in low glucose (2.5mM) and low magnesium (0.08mM) media to mimic the TME. Cell viability was assessed using Titer-Glow, Pico Green and colony formation assays. Cellular and mitochondrial ROS levels were determined via DCFDA and Mito-SOX assays using colorimetric and flow cytometry analysis. The therapeutic potential of ivosidenib, was evaluated through cell proliferation (Cell Trace assay), cell cycle arrest (BrdU) assay via flow cytometry and immunofluorescence, and apoptosis detection (Annexin-V/PI staining). In vivo studies employed orthotopic and autochthonous murine models of PDAC to assess drug efficacy and its impact on immune cell infiltration in the TME. Our data revealed that targeting wtIDH1 suppress cell proliferation and DNA synthesis and elevated cellular and mitochondrial ROS levels leading to increased apoptosis. In orthotropic pancreatic murine models of pancreatic cancer, ivosidenib treatment significantly increased the infiltration of immune cells (CD45+), and CD4+ T cells in particular, including naïve T (CD45RA) and central memory T cells (CD45RO). Additionally CD127 expression was enhanced, promoting the survival and proliferation of naïve and memory T cells, potentially boosting anti-tumor immunity. Notably, treatment led to reduction of anti-inflammatory M2-like monocytes and adaptive immunity associated CD8+T cells, suggesting reshaped immune landscape favoring antitumor responses. Wild-type IDH1 plays a critical role in tumorigenesis and chemoresistance in pancreatic cancer. Our data demonstrates that IDH1 inhibition not only reduces cancer cell proliferation in vitro but also remodels the TME in in vivo, enhancing immune responsiveness. Modulation of the TME via IDH1 inhibition offers a promising avenue to improve efficacy of existing therapies, including chemotherapy and immune checkpoint inhibitors as a part of combination treatment strategies. Citation Format: Priyashree Sunita, Soubhi Tahhan, Mehrdad Zarei, Christina S. Boutros, Omid hajjihassani, Hallie J Graor, Faith Nakazzi, Parnian Naji, Claudia Marcela Diaz, Jordan M Winter. Wildtype IDH1 blockade as a strategy to modulate the tumor microenvironment and boost immune responses in pancreatic cancer [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 3288.