Disruption of Fibroblast MYD88 Signaling Promotes Antitumor Immunity in Pancreatic Ductal Adenocarcinoma [scRNAseq_col1a1myd88]
Pancreatic ductal adenocarcinoma (PDAC) continues to carry a dismal prognosis. The disease is characterized by a uniquely dense fibrotic matrix generated by cancer-associated fibroblasts (CAFs). We have previously demonstrated that fibroblast-driven chronic inflammation suppresses T cell function through a MYD88-dependent mechanism. While extensively studied in myeloid cells, the role of MYD88 signaling in CAFs and its effects on PDAC remain poorly understood. In this study, we identify a MYD88-driven inflammatory CAF population in PDAC using a combination of bulk, single-cell, and spatial transcriptomic studies. Using an innovative collagen gel implantation model, we demonstrate that loss of MYD88 in CAFs enhances T cell infiltration and suppresses tumor growth. Combining MYD88 inhibition with immune checkpoint blockade significantly reduces tumor size and enhances antitumor immune responses, underscoring its potential as a therapeutic target in PDAC. Overall design: Following implantation of the KPC-seeded collagen gels into tamoxifen induced Col1a1CreERT2 MyD88fl/fl mice or control mice, tumors were harvested and dissociated into single cells using the Miltenyi Mouse Tumor Dissociation Kit and analyzed using scRNA-seq.