Abstract 3269: LRRC15/COL11A1+cancer-associated fibroblasts drive immunosuppression and chemotherapy resistance in pancreatic ductal adenocarcinoma

Background and Objectives: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly immunosuppressive tumor microenvironment (TME), which contributes to immune evasion, chemotherapy resistance, and poor prognosis. Cancer-associated fibroblasts (CAFs) are key components of the TME and are closely associated with tumor progression. This study investigated the role of LRRC15/COL11A1+ CAFs in shaping the TME, mediating immunosuppression, and driving chemotherapy resistance in PDAC. Methods and Results: Using single-cell transcriptomic analysis, we identified a CAF subset with co-expression of LRRC15 and COL11A1, which was significantly associated with reduced CD8+ T cell infiltration and increased infiltration of MARCO+ macrophages. These LRRC15/COL11A1+ CAFs were enriched in chemotherapy non-responsive groups and exhibited higher activity in modulating the immune microenvironment by secreting soluble factors such as TGF-β, GAS6, GRN, EGF, VEGF, and CXCL12, which interact with myeloid cells and T cells. To study the temporal dynamics of LRRC15/COL11A1+ CAFs during chemotherapy, we established ultrasound-guided orthotopic PDAC models in mice and administered FIRINOX-based chemotherapy. Serial tumor biopsies were collected from the same tumor before treatment and one and two weeks post-treatment, and at treatment endpoint. Transcriptomic analysis of sequential biopsy samples using ClusterGVis revealed downregulation of various immune response-related pathways (e.g., T-cell receptor signaling, natural killer cell-mediated cytotoxicity, and allograft rejection) after chemotherapy. In contrast, immunosuppressive cytokines including CCL12, CCL2, CCL9, CXCL12, CXCR1, CXCR4, CCR2, CCR5, and IL10, were all significantly upregulated. Additionally, marker genes of LRRC15/COL11A1+ CAFs were also upregulated, recapitulating findings in chemotherapy-treated PDAC patients. We found high correlation of COL11A1 with LRRC15. Multiplex immunofluorescence of the biopsy tissues showed an increase in COL11A1+ CAFs after chemotherapy, which was accompanied by reductions in CD8+ and CD4+ T cell infiltration, and increase in MARCO+ macrophage infiltration. Using a new genetic mouse model we observed an increase in CD8+ T cell infiltration upon diphteria toxin-mediated targeted genetic ablation of COL11A1+ CAFs. Conclusions: LRRC15/COL11A1+ CAFs reshape the TME by immunosuppression and contribute to chemotherapy resistance in PDAC. Targeting LRRC15/COL11A1+ CAFs may represent a potential strategy to enhance immune responses and improve the efficacy of chemotherapy of PDAC. Citation Format: Juanfei Peng, Kristina Althoff, Sven-Thorsten Liffers, Luay Farah, Marija Trajkovic-Arsic, Rui Fang, Savvatakis Konstantinos, Jan Mengeler, Stefan Selbert, Doron Shmerling, Phyllis Fung-Yi Cheung, Jens T. Siveke. LRRC15/COL11A1+cancer-associated fibroblasts drive immunosuppression and chemotherapy resistance in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3269.