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Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation

1
Department of Clinical Medicine, Faculty of Health Sciences, UiT-The Arctic University of Norway, 9037 Tromsø, Norway
2
Department of Radiation Oncology, University Hospital of Northern Norway, 9038 Tromsø, Norway
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(5), 689; https://doi.org/10.3390/cancers11050689 (registering DOI)
Received: 23 April 2019 / Revised: 13 May 2019 / Accepted: 14 May 2019 / Published: 17 May 2019
(This article belongs to the Special Issue Tumor Radioresistance)
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Abstract

The 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
Keywords: cancer-associated fibroblasts; CAFs; ionizing radiation; radiotherapy; macrophages; immunoregulation; immunosuppression cancer-associated fibroblasts; CAFs; ionizing radiation; radiotherapy; macrophages; immunoregulation; immunosuppression
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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.

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