Abstract A019: Epigenetic Tumor Suppressor KMT2D Shapes the Immune Landscape in Pancreatic Cancer

Abstract KMT2D (known as Mll4 in mice) is a histone methyltransferase and a critical epigenetic regulator frequently mutated across a range of cancers. Analysis of TCGA database indicates that alterations in the KMT2D gene – including mutations and changes in expression – occur in approximately 11% of pancreatic cancer patients. Our previous research demonstrated that loss of KMT2D in human pancreatic cancer cells induces epithelial-to-mesenchymal transition (EMT) in tumor cells, leading to more aggressive disease progression. In the current study, we performed bulk RNA sequencing on Mll4 knockdown mouse pancreatic cancer cells (KPC7940), alongside proteomic profiling of their conditioned media. This analysis revealed significant changes in the expression of genes encoding secreted proteins, many of which are involved in immune cell signaling pathways, including TNF-alpha signaling via NF-kB, IL-6/JAK/STAT3 signaling pathway and IL-2/STAT5 signaling pathway. These findings led us to hypothesize that KMT2D loss not only promotes intrinsic tumor cell changes but also remodels the immune microenvironment, potentially contributing to enhanced tumor aggressiveness. To further investigate this, we developed a mouse model of pancreatic cancer with pancreas-specific knockout of Mll4 (KPCM: Kras G12D/+ ; Trp53 R172H/+ ; Ptf1a-Cre; Mll4SET flox/flox ). Strikingly, KPCM mice developed pancreatic cancer as early as 3 weeks of age, compared to the typical onset at 16-20 weeks in KPC mice without Mll4 knockout. Median survival of KPCM animals was 24 days compared 126.5 days for KPC animals. Immunohistochemical analysis for Ki-67 confirmed a markedly higher proliferative rate in KPCM tumors. To characterize the tumor immune microenvironment, we performed single-cell RNA sequencing on pancreata from both KPC and KPCM mice. We observed a substantial increase in myeloid cell population in KPCM tumor. Moreover, NK/T cells in KPCM pancreata expressed more immunosuppressive markers, including Ctla4, Cd274 and Pdcd1. Collectively, our study underscores the pivotal role of KMT2D in orchestrating both tumor-intrinsic and microenvironmental processes that drive pancreatic cancer progression. Elucidating the mechanisms by which KMT2D loss reprograms the immune landscape may reveal novel immunomodulatory therapeutic targets for this devastating malignancy. Citation Format: Hongsun Chae. Kim, Heizel Acosta, Shungang Zhang, Ranga Sudharshan, Sargis Shameon, Marina Pasca di Magliano, Jiaqi Shi. {Abstract title} [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 A019.