title: Ionizing radiation modulates human macrophages towards a pro-inflammatory phenotype preserving their pro-invasive and pro-angiogenic capacities.
abstract: In order to improve the efficacy of conventional radiotherapy, attention has been paid to immune cells, which not only modulate cancer cell response to therapy but are also highly recruited to tumours after irradiation. Particularly, the effect of ionizing radiation on macrophages, using therapeutically relevant doses, is not well understood. To evaluate how radiotherapy affects macrophage behaviour and macrophage-mediated cancer cell activity, human monocyte derived-macrophages were subjected, for a week, to cumulative ionizing radiation doses, as used during cancer treatment (2 Gy/fraction/day). Irradiated macrophages remained viable and metabolically active, despite DNA damage. NF-kappaB transcription activation and increased Bcl-xL expression evidenced the promotion of pro-survival activity. A significant increase of pro-inflammatory macrophage markers CD80, CD86 and HLA-DR, but not CCR7, TNF and IL1B was observed after 10 Gy cumulative doses, while anti-inflammatory markers CD163, MRC1, VCAN and IL-10 expression decreased, suggesting the modulation towards a more pro-inflammatory phenotype. Moreover, ionizing radiation induced macrophage morphological alterations and increased their phagocytic rate, without affecting matrix metalloproteases (MMP)2 and MMP9 activity. Importantly, irradiated macrophages promoted cancer cell-invasion and cancer cell-induced angiogenesis. Our work highlights macrophage ability to sustain cancer cell activities as a major concern that needs to be addressed to improve radiotherapy efficacy.
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal.|INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-465, Portugal.|FEUP-Faculty of Engineering, University of Porto, Porto, 4200-465, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Teresa Pinto
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal.|INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-465, Portugal.|ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, 4050-313, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Laranjeiro Pinto
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal.|INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-465, Portugal.|FEUP-Faculty of Engineering, University of Porto, Porto, 4200-465, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Patrícia Cardoso
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal.|INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-465, Portugal.
authors.forename: Cátia
authors.initials: C
authors.lastname: Monteiro
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal.|IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, 4200-465, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Teixeira Pinto
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal.|IBMC-Institute for Molecular and Cell Biology, University of Porto, Porto, 4200-465, Portugal.
authors.forename: André
authors.initials: A
authors.lastname: Filipe Maia
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal.|IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, 4200-465, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Castro
authors.affiliation: Radiotherapy Service, Centro Hospitalar S. João, EPE, Porto, 4200-319, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Figueira
authors.affiliation: Radiotherapy Service, Centro Hospitalar S. João, EPE, Porto, 4200-319, Portugal.
authors.forename: Armanda
authors.initials: A
authors.lastname: Monteiro
authors.affiliation: Radiotherapy Service, Centro Hospitalar S. João, EPE, Porto, 4200-319, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Marques
authors.affiliation: Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, B-9000, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Mareel
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal.|INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-465, Portugal.|ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, 4050-313, Portugal.
authors.forename: Susana Gomes
authors.initials: SG
authors.lastname: Dos Santos
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal.|IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, 4200-465, Portugal.|Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, 4200-319, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal.|INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-465, Portugal.|ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, 4050-313, Portugal.
authors.forename: Mário
authors.initials: M
authors.lastname: Adolfo Barbosa
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
authors.forename: Sónia
authors.initials: S
authors.lastname: Rocha
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal.|INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-465, Portugal.|Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, 4200-319, Portugal.
authors.forename: Maria
authors.initials: M
authors.lastname: José Oliveira
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D016764:Cell Polarity; D048430:Cell Shape; D002470:Cell Survival; D004249:DNA Damage; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000502:physiology* / Q000528:radiation effects*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000276:immunology*; D010641:Phenotype; D015398:Signal Transduction; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; C508609:IL10 protein, human; D008070:Lipopolysaccharides; D051020:bcl-X Protein; D016753:Interleukin-10; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9