A hallmark of pancreatic tumors is their highly desmoplastic stroma composed of fibroblasts, immune cells and a dense network of collagen fibers. Pancreatic tumor-associated macrophages are considered M2 macrophages and are thought to support tumor progression through the engagement of multiple mechanisms that promote immune tolerance. Another well-documented role of M2 macrophages is the remodeling of the tumor stroma via collagen production and degradation, with the latter being mediated by mannose receptor (Mrc1)-mediated endocytosis of collagen. Given our previous work showing that protein scavenging by tumor cells can be utilized as a nutrient delivery mechanism, we set out to investigate the functional significance of collagen scavenging by macrophages. We have found that, in M2 macrophages, Mrc1-mediated collagen internalization and subsequent lysosomal degradation leads to a metabolic reprogramming that is characterized by the accumulation of collagen-derived intracellular free amino acids and an increase in arginine biosynthesis. The increase in arginine levels results in a significant upregulation of inducible nitric oxide synthase (iNOS) and arginase 1 (ARG1), giving rise to an M1/M2 hybrid macrophage. Moreover, iNOS+ARG1+ double-positive macrophages are present in the microenvironment of pancreatic tumors. The functional contribution of this cell population to pancreatic tumorigenesis is being investigated. Our findings suggest a new modality for the functional modulation of tumor-associated macrophages through the coupling of extracellular matrix remodeling to protein scavenging.
This abstract is also being presented as Poster A58.
Citation Format: Madeleine M. LaRue, Jane Cullis, Dafna Bar-Sagi. Collagen scavenging alters macrophage phenotype in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR22.