745 Spatial enrichment of tumor-associated macrophage subsets near cancer-associated fibroblasts identifies distinct stromal niches in PDAC
Year: 2026
Type: conference-abstract
Abstract: Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stromal barrier that impedes therapeutic efficacy and restricts immune cell infiltration into tumors. Composed of cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), the barrier is thought to arise from their interactions, yet the mechanisms remain poorly understood. Both CAFs and TAMs are heterogeneous populations of diverse phenotypes that promote tumor progression. TAMs can be broadly divided into pancreatic resident TAMs (PR-TAMs) and monocytic-derived TAMs (Mo-TAMs). Prior efforts targeting TAMs to impact the tumor microenvironment (TME) have largely failed in PDAC. Deciphering the spatial organization of TAM subsets relative to CAFs and tumor cells may identify stromal niches that can be therapeutically targeted. We hypothesized that distinct TAM subsets occupy specialized stromal niches in association with CAFs in the PDAC TME. To test this, we examined the spatial relationships between CAFs, TAM subsets, and tumor cells in human PDAC tissue sections.Methods Resected archival tissues were obtained from patients with primary PDAC who were treatment naïve (n = 12) and FOLFIRINOX treated (n = 12) and stained with multiplex immunofluorescence panels to detect PR-TAMs (CD68 +), Mo-TAMs (CD68+ CCR2+), tumor cells (CK19+), and activated CAFs (αSMA+). Imaging and cell detection were performed using the Zeiss Axioscan and QuPath, followed by spatial analysis in R.Results In FOLFIRINOX-treated PDAC tumors, PR-TAM density was significantly increased compared with treatment-naïve tumors (median 348 vs. 73 cells/mm 2, p = 0.041), whereas Mo-TAMs remained unchanged (median 113 vs. 78 cells/mm2, p = 0.216). Proximity analysis revealed PR-TAMs localized significantly closer to CK19+ tumor cells than Mo-TAMs in both treatment-naïve (35.6 vs. 90.2 µm, p = 0.009) and treated tumors (44.8 vs. 115.7 µm, p = 0.03). Similarly, PR-TAMs localized closer to αSMA+ CAFs in treated tumors compared with Mo-TAMs (98.55 vs. 319.2 µm, p < 0.0005). Tumor nest analyses further revealed enrichment of both PR-TAMs and αSMA+ CAFs around smaller tumor nests, whereas Mo-TAMs were more frequently associated with larger nests.Conclusions PR-TAMs exhibit distinct spatial enrichment near CAFs and tumor cells, identifying them as candidate mediators of stromal organization in PDAC. These findings support further investigation of PR-TAM-directed therapeutic strategies to disrupt stromal niches in PDAC.
Institution: Emory University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225158277