Targeting MyD88 in Cancer-Associated Fibroblasts Enhances Antitumor Immunity in Pancreatic Cancer
Rosyli Reveron-Thornton, Mahsa Fallah, Maria Korah, Amanda Gonçalves, Peter Y Xie, Chuner E Guo, James P Agolia, Andrea E Delitto, Renceh AB Flojo, Angela D Tabora, Amanda R Kirane, Monica M Dua, Brendan C Visser, Byrne Lee, George A Poultsides, Derrick C Wan, Jeffrey A Norton, Deshka S Foster, Michael T Longaker, and Daniel Delitto
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma enriched with cancer-associated fibroblasts (CAFs) that modulate the tumor immune microenvironment and contribute to immune evasion. Among CAF subtypes, inflammatory CAFs (iCAFs) modulate the tumor microenvironment through cytokine secretion and extracellular matrix remodeling. MyD88, an innate immune signaling adaptor activated by Toll-like receptors (TLR) and IL-1 receptors (IL-1R), is highly expressed in iCAFs, potentially explaining the immunosuppressive properties of CAFs. This study examines the CAF and immune microenvironmental alterations following the ablation of fibroblast-specific MyD88 signaling in iCAFs within PDAC tumors.
Methods: A novel transgenic mouse model with a tamoxifen-induced, fibroblast-specific MyD88 gene knockout (Col1a1CreERT2; MyD88fl/fl) was implanted with a collagen gel containing KPC cells. PDAC tumors were harvested upon reaching 1 cm in diameter, and their microenvironments were analyzed using single-cell RNA sequencing (scRNA-seq) and immunohistochemistry (IHC).
Results: Single-cell RNA-seq revealed a reduction in iCAFs and an upregulation of T cell activation markers (Pdcd1, Tnfrsf9, and Cd44). Furthermore, Col1a1CreERT2MyD88fl/fl CAFs exhibited increased expression of genes and transcription factors involved in oxidative stress responses (Srxn1, Nfe2l2, and Hif1a) and alternative inflammatory signaling pathways (Txnrd1, JunB, and Jun). We also demonstrate that fibroblast-specific MyD88 inhibition led to a statistically significant decrease in tumor size (p < 0.0001) and an increase in intratumoral T cell infiltration, as observed by IHC.
Conclusions: These findings underscore the role of iCAFs in immune modulation and suggest that targeting specific CAF subpopulations could enhance antitumor immunity in PDAC.