Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation
AbstractThe abilities of cancer-associated fibroblasts (CAFs) to regulate immune responses in the context of radiotherapy remain largely unknown. This study was undertaken to determine whether ionizing radiation alters the CAF-mediated immunoregulatory effects on macrophages. CAFs were isolated from freshly-resected non-small cell lung cancer tumors, while monocyte-derived macrophages were prepared from peripheral blood of healthy donors. Experimental settings included both (CAF-macrophage) co-cultures and incubations of M0 and M1-macrophages in the presence of CAF-conditioned medium (CAF-CM). Functional assays to study macrophage polarization/activation included the expression of cell surface markers, production of nitric oxide, secretion of inflammatory cytokines and migratory capacity. We show that CAFs promote changes in M0-macrophages that harmonize with both M1-and M2-phenotypes. Additionally, CAFs inhibit pro-inflammatory features of M1-macrophages by reducing nitric oxide production, pro-inflammatory cytokines, migration, and M1-surface markers expression. Radiation delivered as single-high dose or in fractioned regimens did not modify the immunoregulatory features exerted by CAFs over macrophages in vitro. Protein expression analyses of CAF supernatants showed that irradiated and non-irradiated CAFs produce approximately the same protein levels of immunoregulators. Thus, CAF-derived soluble factors mediate measurable changes on uncommitted macrophages and down-regulate pro-inflammatory features of M1-polarized macrophages. Notably, ionizing radiation does not curtail the CAF-mediated immunosuppressive effects. View Full-Text
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Berzaghi, R.; Ahktar, M.A.; Islam, A.; Pedersen, B.D.; Hellevik, T.; Martinez-Zubiaurre, I. Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation. Cancers 2019, 11, 689.
Berzaghi R, Ahktar MA, Islam A, Pedersen BD, Hellevik T, Martinez-Zubiaurre I. Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation. Cancers. 2019; 11(5):689.Chicago/Turabian Style
Berzaghi, Rodrigo; Ahktar, Muhammad A.; Islam, Ashraful; Pedersen, Brede D.; Hellevik, Turid; Martinez-Zubiaurre, Inigo. 2019. "Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation." Cancers 11, no. 5: 689.
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