Abstract B020: Charting the cellular heterogeneity of primary and metastatic PDAC microenvironment

Abstract

Abstract Cancer-associated fibroblasts (CAFs) are important regulators of tumor progression and therapeutic response in PDAC, with several functionally diverse populations now identified. However, while CAF populations with similar transcriptional characteristics have been identified across different tissues, emerging data suggests that these populations may diverge functionally. For example, whereas antigen presenting CAFs (apCAFs) have been suggested to promote immune evasion in PDAC, apCAFs have been associated with anti-tumor immunity in lung cancer. Thus, high resolution mapping of the microenvironment in both primary and metastatic tumors is required to define tissue specific and conserved subsets for functional interrogation. We deployed cytometry by time of flight (CyTOF) to annotate stromal and immune subsets in healthy and tumor bearing murine pancreas, liver and lung. Spatial proximity of tumor and host cells was further annotated using sLP-mCherry, a secreted lipo-permeable form of mCherry. In total, we annotated 50.3 million cells across normal and tumor bearing tissues. Stromal fibroblast populations were highly divergent across both healthy and tumor bearing tissues. Commonly used markers were expressed in a manner dominated by tissue of origin, with less than 10% of fibroblasts and CAFs displaying common phenotypes across tissues. For example, aSMApos/PDGFRalow myCAFs were abundant in lung and liver, Ly6cpos/PDGFRapos/aSMAlow iCAFs were more abundant in the pancreas and MHCIIpos/CD74pos apCAFs were more dominant in lung. In contrast, most immune subsets, with exception of alveolar macrophages and Kupfer cells, were consistently observed across all tissues analysed albeit at different abundances. Tumors arising from epithelial and mesenchymal PDAC cells induce unique changes in CAF subset abundances where epithelial tumors are enriched for myCAFs and mesenchymal tumors induce more apCAFs. These observations were consistent across tumor bearing liver and lung. MyCAFs and PD-L1 or PDL-2 expressing macrophages were generally more proximal to epithelial tumor cells, whereas tumors originating from mesenchymal PDAC cells were enriched for antigen-experienced T cells. Taken together these analyses reveal tissue specific effects on the emerging microenvironment, with shared properties emerging from immune and mesenchymal niche composition. Citation Format: Adrian Blanco-Gomez, Catherine Felton, Antonia Banyard, Claus Jorgensen. Charting the cellular heterogeneity of primary and metastatic PDAC microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B020.