Decoding the stromal niches of antigen-presenting cancer-associated fibroblast in pancreatic ductal adenocarcinoma

/Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a dismal 5-year survival rate of only 12%. A hallmark of PDAC is the extensive desmoplastic stroma, which can comprise up to 90% of the tumor mass, driven largely by the expansion of cancer-associated fibroblasts (CAFs). Through single-cell RNA sequencing (scRNA-seq), our group and others have identified distinct CAF subpopulations in PDAC. These include myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and a third, less understood population: antigen-presenting CAFs (apCAFs), which are defined by the expression of major histocompatibility complex (MHC) class II molecules. Using robust lineage-tracing techniques, we demonstrated that apCAFs originate from mesothelial cells. Importantly, apCAFs induce regulatory T cells (Tregs) through an antigen-dependent mechanism. Our spatial transcriptomics studies further revealed that apCAFs form specialized stromal niches that are enriched in chemoresistant cancer cells, myCAFs, and Tregs. These findings underscore the critical role of apCAFs in modulating the tumor microenvironment, with direct implications for immune regulation and therapy resistance. In this proposal, we aim to elucidate the interactions between apCAFs and other cell types within these unique stromal niches. Furthermore, we will examine the therapeutic potential of pharmacologically inhibiting apCAF formation and the key apCAF paracrine signal to overcome resistance to chemo- and immunotherapies. The insights gained from this study will significantly advance our understanding of stromal regulation by apCAFs and could lead to novel strategies for targeting CAFs specifically in PDAC and potentially other cancer types. The use of animal models is necessary for this project because the complex interactions among apCAFs, immune cells, and cancer cells within the tumor microenvironment cannot be adequately studied using in vitro systems alone. These models allow us to trace cell lineage, evaluate gene-specific functions in vivo, and test therapeutic strategies in physiologically relevant settings. Project Number: 1R01CA303246-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Huocong Huang | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $501,803 | Activity Code: R01 | Study Section: Mechanisms of Cancer Therapeutics B Study Section[MCTB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11366758