Abstract A021: Cancer-associated fibroblast-derived CXCL12 as a potential therapeutic target for pancreatic ductal adenocarcinoma immunotherapy

Abstract Introduction: Cancer-associated fibroblasts (CAFs) are the major non-neoplastic component of PDAC. CAFs facilitate tumor proliferation and induce immune evasion of cancer cells. Coincidentally, chemokines are a class of small cytokines that guide the migration, activation and localization of cells during development, homeostasis, and inflammation. CAFs and chemokines serve critical functions in the tumor microenvironment (TME) and are increasingly understood to contribute to tumor progression, metastasis, and the overall immune response to cancer. Our objective was to investigate how CAFs and their associated chemokines alter the TME in PDAC, consequently influencing tumor development, and give new therapeutic targets. Method: We analysed three single-cell transcriptomic atlas: GSE212966 (6 PDAC patients), GSE155698 (15 PDAC patients), and GSE214295 (3 PDAC patients) from GEO. According to the standardized pipeline, the 10 × scRNA-seq data were processed using R software, “Seurat” package. We conducted dimension reduction using PCA with the ‘RunPCA’ function. Within this reduced PCA space, clusters were discerned using the KNN algorithm, facilitated by ‘FindNeighbours’ and ‘FindClusters’ functions. We then visualised these clusters employing t-distributed stochastic neighbor embedding with the “RunTSNE”. Moreover, we included heatmaps (‘DoHeatmap’), violin plots (‘VlnPlot’) and TSNEPlots (‘FeaturePlot’), to visualize the expression of recognized chemokines. Following preprocessing and classification, the scRNA dataset was prepared for additional downstream analysis. To analyse cell-cell interactions between CAFs and other cellular categorises in the TME, we used the ‘CellChat’ package. Results: In our investigation of single-cell RNA sequencing of human PDAC, we identified that CXCL12, also known as stromal cell-derived factor-1, is a chemokine abundantly produced by CAFs in PDAC across multiple databases. Its specific receptors CXC receptor 4 (CXCR4) or atypical chemokine receptor 3 (ACKR3, also known as CXCR7) were most expressed in T cells, B cells, macrophages, and neutrophils. Additionally, CAFs communicated extensively with T cells, B cells, macrophages and neutrophils in PDAC, primarily through the CXCL12-CXCR4 and CXCL12-ACKR3 ligand-receptor pairs by analysing cell-cell interactions. Conclusion: CAFs-derived CXCL12-CXCR4 or CAFs-derived CXCL12-ACKR3 ligand-receptor pairings are the main mechanisms by which CAFs interact with T cells, B cells, macrophages, and neutrophils in PDAC. In-depth studies of CAFs-derived CXCL12 and TME interactions, particularly the complicated mechanisms connecting CAFs with cancer cells, immune cells, and other stromal cells, might provide novel strategies for subsequent targeted immunotherapies. Fundings: Hong Kong Theme-based Scheme (T12-201/20-R) Citation Format: Liu Yang, Aiping LU, Fangfei LI. Cancer-associated fibroblast-derived CXCL12 as a potential therapeutic target for pancreatic ductal adenocarcinoma immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A021.