Abstract A63: Macrophages expressing fibroblast activation protein-alpha are a tumor-educated polarization phenotype which facilitates metastasis

Abstract

Abstract Tumor associated macrophages (TAMs) are one of the most abundant stromal cell types in cancer, and promote tumor progression by supporting angiogenesis, immunosuppression, and tumor cell migration. However, there is increasing evidence to suggest that the functions of these cells could be refined to specific subsets. A subset of TAMs identified by the cell surface marker fibroblast activation protein-alpha (FAP) has previously been demonstrated to facilitate immune suppression in an ectopic Lewis lung carcinoma model through its expression of the heme degrading enzyme heme oxygenase-1 (HO-1) (Arnold et al, 2014). Little is known about the origin of these cells, and whether they represent an autonomous population or a polarization phenotype. Here we show in orthotopic mammary 4T1 adenocarcinomas that FAP+ TAMs are a tumor-educated polarization phenotype which is functionally distinct from IL-4/-13 polarized alternatively activated macrophages. In contrast, IL-6 and integrin β1 signaling contribute to FAP+ TAM polarization. In addition to the previously described role of these cells in immune suppression we show that FAP+ TAMs facilitate pulmonary metastasis. FAP+ TAMs are the primary tumoral source of HO-1 and pharmacological inhibition of HO activity reduces pulmonary metastasis in both orthotopic 4T1 adenocarcinomas and aggressive autochthonous murine mammary adenocarcinomas (MMTV-PyMT). Using an in vitro transwell assay, we demonstrate that HO-1 activity by macrophages enhances the transendothelial migration of tumor cells. In vivo HO inhibition does not affect seeding of tumor cells in the lung once these cells have entered the circulation, suggesting that FAP+ TAMs facilitate the intravasation event. Together, these results demonstrate FAP+ TAMs to be a tumor-educated polarization phenotype which facilitates tumor cell metastasis by its expression of HO-1. Arnold, J.N., et al., Tumoral immune suppression by macrophages expressing fibroblast activation protein-α and heme oxygenase-1. Cancer Immunol Res, 2014. 2(2): p. 121-6 Citation Format: Tamara de Koning, Joy M. Burchell, Sandra S. Diebold, James N. Arnold. Macrophages expressing fibroblast activation protein-alpha are a tumor-educated polarization phenotype which facilitates metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A63.