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.

New Mechanisms of Tumor-Associated Macrophages on Promoting Tumor Progression: Recent Research Advances and Potential Targets for Tumor Immunotherapy

“…The recruited heterogeneous populations of TAMs release proangiogenic cytokines and metalloproteinases to promote blood vessel formation within the tumor [19]. Teresa Pinto et al [20] also found that irradiated macrophages promote cancer cell invasiveness and cancer cell-induced angiogenesis. Besides, the abscopal effect may be a crucial factor in evaluation of the prognosis associated with radiotherapy, and TAMs can release secondary bystander signals and play a key role in the secondary bystander effect of photon irradiation [21].…”

Exploring the oncoproteomic response of human prostate cancer to therapeutic radiation using data‐independent acquisition (DIA) mass spectrometry

“…Several pro‐inflammatory and immune‐related proteins with increased abundance were also identified, including CD163, Cathepsins, Myeloperoxidase, S100 Calcium Binding Proteins (Calprotectins), and HLA class II histocompatibility antigen DRα chain. These are strong indicators of macrophage and myeloid cell activation and function, potentially resulting from RT‐induced myeloid cell infiltration . Additionally, there was an overrepresentation of proteins strongly linked to serine protease activity—a well‐described functional element of the innate immune system in driving blood coagulation, inflammation, apoptosis and tissue remodeling .…”

Mechanisms of the alternative activation of macrophages and non-coding RNAs in the development of radiation-induced lung fibrosis

“…Although their DNA was damaged upon irradiation, the macrophages remained viable and metabolically active and at 10 Gy cumulative dose a significant increase in pro-inflammatory macrophage markers CD80, CD86 and HLA-DR was observed, while anti-inflammatory markers CD163, MRC1, VCAN and IL-10 decreased. These results suggest that FIR facilitates the polarization of macrophages towards pro-inflammatory phenotype[40]. …”