Abstract A061: TIGIT-mediated immune suppression in KMT2D-mutant pancreatic cancer

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to immune therapies. There are few biomarkers to guide the selection of patients likely to benefit from available immunotherapyies. Recent whole genome sequencing reveal that KMT2D, a histone-modifying enzyme, is mutated in up to 5% of PDAC cases. Our prior work established a tumor-suppressive role for KMT2D in regulating pancreatic cancer cell plasticity, especially showing that TGF-β-driven microRNA-147b silences KMT2D post-transcriptionally, and that KMT2D loss induces activin A secretion, triggering a noncanonical p38 MAPK pathway and promoting a mesenchymal phenotype. However, the impact of KMT2D deficiency on the tumor microenvironment (TME) remains unexplored. A comprehensive analysis comparing immune composition, immune checkpoint expression, and tumor-immune cell interactions in KMT2D-deficient versus wild-type PDAC has not been performed. Methods: We profiled the immune landscape in human PDAC tissues (n=5 KMT2D-mutant, n=8 wild-type [WT]) using tyramide signal amplification multiplex fluorescent immunohistochemistry (mfIHC) with two distinct antibody panels (Panel 1: PanCK, CD163, PD-L1, CD3, CD8, FoxP3; Panel 2: PanCK, CD163, CD3, CD8, TIGIT, TIM3). Eighty-six tumor-enriched regions were analyzed using InForm Cell Analysis software. For transcriptomic profiling, single-cell RNA sequencing (scRNA-seq) data from 30 PDAC patients were analyzed using the Seurat pipeline. All statistical analyses were conducted in R. Results: KMT2D-mutant PDACs exhibited increased expression of the immune checkpoint TIGIT on CD4 T cells. Cellular engagement analysis demonstrated more CD4 T cells in proximity to epithelial cells (tumor cells) expressed TIGIT in KMT2D-mutant PDACs compared to WT PDACs. Additionally, disrupted immune cell crosstalk, as evidenced by altered spatial correlations in the proximity of antigen presenting cells (APC) to CD4 T cells, and in the distance between tumor cells and CD8 T cells in the mutant tumors. scRNA-seq analyses corroborated the enhanced TIGIT and CTLA4 expression, as well as the upregulation of the exhaustion-associated transcription factor PRDM1 in CD4 T cells from KMT2D-low PDACs, supporting the emergence of a dysfunctional, immunosuppressive CD4 T cell phenotype. Conclusion: Our findings reveal that KMT2D mutations are associated with an immunosuppressive tumor microenvironment in PDAC, marked by CD4 T cell dysfunction and upregulation of the immune checkpoint TIGIT. These results nominate TIGIT as a promising therapeutic target for this subset of PDAC patients and provide new insight into the mechanisms of immunotherapy resistance in KMT2D-mutant tumors. Citation Format: Shungang Zhang, Elaina Daniels, Jake McGue, Hongsun C. Kim, Ranga Sudharshan, Dafydd Thomas, Timothy Frankel, Jiaqi Shi. TIGIT-mediated immune suppression in KMT2D-mutant pancreatic cancer [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 A061.