(762) Epigenetic Tumor Suppressor KMT2D Shapes the Immune Landscape in Pancreatic Cancer

Introduction/Rationale: KMT2D (known as Mll4 in mice) is a histone methyltransferase and a critical epigenetic regulator frequently mutated across a range of cancers. TCGA data indicate alterations in KMT2D, including mutations and changes in expression, in approximately 11% of pancreatic cancer patients. Our previous research showed that KMT2D loss in human pancreatic cancer cells induces epithelial-to-mesenchymal transition (EMT), promoting aggressive disease progression. We hypothesized that KMT2D loss not only drives intrinsic tumor changes but also remodels the immune microenvironment.

Methods: We performed bulk RNA sequencing on Mll4 knockdown mouse pancreatic cancer cells (KPC7940) and proteomic profiling of their conditioned media to identify changes in secreted proteins. Pathway analysis focused on TNF-alpha/NF-kB, IL-6/JAK/STAT3, and IL-2/STAT5 signaling. A pancreas-specific Mll4 knockout model (KPCM: KrasG12D/+; Trp53R172H/+; Ptf1a-Cre; Mll4SETflox/flox) was generated to assess tumor progression in vivo. Tumor proliferation was evaluated by Ki-67 immunohistochemistry. Single-cell RNA sequencing was used to characterize the immune microenvironment in KPC and KPCM tumors.

Results: KPCM mice developed pancreatic cancer by 3 weeks compared to 16–20 weeks in KPC controls, with median survival of 24 vs 126.5 days. Ki-67 staining confirmed higher proliferation in KPCM tumors. Bulk RNA-seq and proteomic analysis revealed altered expression of secreted proteins enriched in inflammatory and immunomodulatory pathways. Single-cell RNA sequencing showed increased myeloid populations and NK/T cells expressing immunosuppressive markers, including CTLA4, CD274, and PDCD1, in KPCM tumors.

Conclusion: KMT2D plays a pivotal role in orchestrating both tumor-intrinsic and microenvironmental processes that drive pancreatic cancer progression. Understanding how KMT2D loss reprograms the immune landscape may uncover novel immunomodulatory therapeutic targets for pancreatic cancer.