Abstract B076: Tumor cell-intrinsic KMT2D loss regulates T cell function through FN1 signaling in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies and is characterized by a profoundly immunosuppressive tumor microenvironment (TME) that limits the efficacy of current therapies. KMT2D (Mll4 in mice) is a histone H3K4 methyltransferase and critical epigenetic regulator that is altered in approximately 11% of PDAC cases, based on analysis of The Cancer Genome Atlas (TCGA). Our previous studies demonstrated that KMT2D loss promotes epithelial-to-mesenchymal transition (EMT) and tumor progression in human PDAC cells while remodeling the tumor immune microenvironment in vivo. To define how KMT2D loss reshapes epithelial–immune communication, we performed single-cell RNA sequencing on pancreata from age-matched KPC, stage-matched KPC-T, and our laboratory-generated pancreas-specific KMT2D-deficient PDAC mouse model (KPCM; LSL-KrasG12D/+^; LSL-Trp53R172H/+^; Ptf1a-Cre; Mll4^SETflox/flox). CellChat analysis revealed genotype-dependent remodeling of epithelial–immune communication and identified a distinct FN1-associated epithelial–T-cell signaling network selectively enriched in KPCM tumors compared with KPC/KPC-T. Given the established role of FN1 in extracellular matrix remodeling and integrin-mediated tumor–immune interactions, we further characterized these interactions by subclustering T cells into CD4 and CD8 populations followed by ligand–receptor analysis. FN1–ITGA4/ITGB7 emerged as the predominant predicted epithelial-to-CD8 T-cell interaction, while additional FN1-associated interactions, including FN1–ITGA4/ITGB1, were identified in CD4 T cells. Consistent with the single-cell transcriptomic findings, FN1 expression was significantly increased in KMT2D-deficient mouse and human PDAC cells and independently validated by RT-qPCR, while receptor expression analyses confirmed expression of the corresponding integrin receptors within the relevant T-cell populations. Collectively, these findings identify an FN1-associated epithelial–T-cell communication network associated with KMT2D loss and suggest a mechanism through which tumor-intrinsic epigenetic alterations remodel tumor–immune interactions within the PDAC microenvironment. These findings provide a foundation for future functional studies investigating FN1-associated signaling as a potential therapeutic target in PDAC.