Abstract
Simple SummaryMacrophages are a major component of the pancreatic tumor microenvironment, and their increased abundance is associated with poor patient survival. Given the multi-faceted role of macrophages in promoting pancreatic tumor development and progression, these cells represent promising targets for anti-cancer therapy.Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of less than 10%. Macrophages are one of the earliest infiltrating cells in the pancreatic tumor microenvironment, and are associated with an increased risk of disease progression, recurrence, metastasis, and shorter overall survival. Pre-clinical studies have demonstrated an unequivocal role of macrophages in PDAC by contributing to chronic inflammation, cancer cell stemness, desmoplasia, immune suppression, angiogenesis, invasion, metastasis, and drug resistance. Several macrophage-targeting therapies have also been investigated in pre-clinical models, and include macrophage depletion, inhibiting macrophage recruitment, and macrophage reprogramming. However, the effectiveness of these drugs in pre-clinical models has not always translated into clinical trials. In this review, we discuss the molecular mechanisms that underpin macrophage heterogeneity within the pancreatic tumor microenvironment, and examine the contribution of macrophages at various stages of PDAC progression. We also provide a comprehensive update of macrophage-targeting therapies that are currently undergoing clinical evaluation, and discuss clinical challenges associated with these treatment modalities in human PDAC patients.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a5-year survival rate of less than 10% and is the seventh leading cause of cancer-related death worldwide [1,2]
Loss of monocyte-derived macrophages has limited effects on PDAC progression, while depletion of tissue-resident macrophages significantly impairs tumor growth [17]. These results suggest that tissue-resident macrophages are more potent drivers of PDAC compared to their monocyte-derived counterparts, and are indispensable for tumor development
hematopoietic stem cell (HSC)/monocyte-derived macrophages have well-recognized roles in antigen presentation, immunosuppression, and therapeutic resistance [17,18,19,20,21]. While these findings suggest that embryonic- and HSC/monocyte-derived macrophages have distinct and non-redundant roles, other subsets derived from these two tissue origins are expected given the importance of microenvironmental cues in shaping macrophage plasticity
Summary
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a. A hallmark of PDAC is the presence of a dense desmoplastic (fibrotic) reaction that surrounds cancer cells and can account for up to 80% of the tumor mass [10]. It is comprised of a heterogeneous population of cells (e.g., fibroblasts, stellate cells, immune cells, endothelial cells), acellular components (e.g., fibrin, collagen, hyaluronic acid, fibronectin, growth factors, cytokines), and is characterized by biophysical features (e.g., low pH, hypoxia, high interstitial pressure) that interact to promote tumor growth and limit therapeutic response [11]. We will delineate the contribution of TAMs in PDAC, and explore how they may be utilized as therapeutic targets
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