Irradiation Promotes an M2 Macrophage Phenotype in Tumor Hypoxia

Abstract

Macrophages display different phenotypes with distinct functions and can rapidly respond to environmental changes. Previous studies on TRAMP-C1 tumor model have shown that irradiation has a strong impact on tumor microenvironments. The major changes include the decrease of microvascular density, the increase of avascular hypoxia, and the aggregation of tumor-associated macrophages in avascular hypoxic regions. Similar changes were observed no matter the irradiation was given to tissue bed before tumor implantation (pre-IR tumors), or to established tumors (IR tumors). Recent results on three murine tumors, TRAMP-C1 prostate adenocarcinoma, ALTS1C1 astrocytoma, and GL261 glioma, further demonstrate that different phenotypes of inflammatory cells are spatially distributed into different microenvironments in both IR and pre-IR tumors. Regions with avascular hypoxia and central necrosis have CD11bhigh/Gr-1+ neutrophils in the center of the necrotic area. Next to them are CD11blow/F4/80+ macrophages that sit at the junctions between central necrotic and surrounding hypoxic regions. The majority of cells in the hypoxic regions are CD11blow/CD68+ macrophages. These inflammatory cell populations express different levels of Arg I. This distribution pattern, except for neutrophils, is not observed in tumors receiving chemotherapy or an anti-angiogenesis agent which also lead to avascular hypoxia. This unique distribution pattern of inflammatory cells in IR tumor sites is interfered with by targeting the expression of a chemokine protein, SDF-1α, by tumor cells, and this also increases radiation-induced tumor growth delay. This indicates that irradiated-hypoxia tissues have distinct tumor microenvironments that favor the development of M2 macrophages and that is affected by the levels of tumor-secreted SDF-1α.

Chemotherapeutic tumor microparticles combining low-dose irradiation reprogram tumor-promoting macrophages through a tumor-repopulating cell-curtailing pathway

“…It has been reported that Treg cells and TAMs both can be enhanced following radiotherapy. [41][42] The dosage of radiotherapy might be a key factor in the reconciliation of this apparent contradiction. 29 LDI has been shown to program macrophage differentiation into an iNOS C /M1 phenotype, leading to normalization of tumor vasculature and facilitation of immune cell entry into tumor sites.…”

Role of Activin A in Immune Response to Breast Cancer

“…However, some chemotherapeutic agents can cause immunogenic cell death and promote anti-tumor immunity (192). Also, despite the antitumor-immune promoting effects of RT, prior irradiation may lead to modification of the tumor microenvironment leading to a more immune-tolerant phenotype (113,193). The net effect of these prior treatments is not clear, but it is likely to have an impact on the immune system and on the effectiveness of cancer immunotherapy.…”

“…There are reports that RT can impair DC function, including cross-priming (109,110). Additionally, RT can contribute to the immunesuppressive tumor microenvironment by recruiting MDSCs and TAMs (76,(111)(112)(113). Tumor-infiltrating Tregs are also enriched after RT (77,114).…”

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“…In addition, inhibition of the PD-1/PD-L1 pathway on T cells has been associated with a potent antitumor activity in mouse tumor models and in clinical trials (71,(115)(116)(117).…”

“…On the other hand, ionizing radiation can also generate chemotactic signals that recruit several myeloid-cell types with distinct roles in T cell suppression (114)(115)(116).…”