Radiation-Induced Fibrotic Tumor Microenvironment Regulates Anti-Tumor Immune Response

Abstract

High linear energy transfer (LET) radiation, such as neutron radiation, is considered more effective for the treatment of cancer than low LET radiation, such as X-rays. We previously reported that X-ray irradiation induced endothelial-to-mesenchymal transition (EndMT) and profibrotic changes, which contributed to the radioresistance of tumors. However, this effect was attenuated in tumors of endothelial-specific Trp53-knockout mice. Herein, we report that compared to X-ray irradiation, neutron radiation therapy reduced collagen deposition and suppressed EndMT in tumors. In addition to the fewer fibrotic changes, more cluster of differentiation (CD8)-positive cytotoxic T cells were observed in neutron-irradiated regrowing tumors than in X-ray-irradiated tumors. Furthermore, lower programmed death-ligand 1 (PD-L1) expression was noted in the former. Endothelial-specific Trp53 deletion suppressed fibrotic changes within the tumor environment following both X-ray and neutron radiation therapy. In particular, the upregulation in PD-L1 expression after X-ray radiation therapy was significantly dampened. Our findings suggest that compared to low LET radiation therapy, high LET radiation therapy can efficiently suppress profibrotic changes and enhance the anti-tumor immune response, resulting in delayed tumor regrowth.

2-Methoxyestradiol Inhibits Radiation-Induced Skin Injuries

“…H&E and Masson's Trichrome staining showed that irradiation increased skin inflammation, skin thickness, and collagen deposition, but these were significantly recovered by post-treatment with 2-ME after irradiation (Figure 2a). It is well known that a single dose of radiation higher than 10 Gy induces severe vascular damages [19]. Immunohistochemistry assay using CD31, an EC marker, showed that the vessel density of irradiated skin significantly decreased compared to that of nonirradiated skin, whereas 1 h before irradiation and 24 h after radiation, 2-ME treatment significantly inhibited the loss of microvessel density and the destruction of microvessels caused by irradiation (Figure 1b).…”

HPV and radiosensitivity of cervical cancer: a narrative review

“…Low-let radiation is oxygen dependent, and hypoxia can lead to radiation resistance. High LET radiation does not require oxygen and directly damages the DNA of tumor cells, which is more effective in killing tumor cells ( 52 ). Compared with HPV+ CC, HPV− CC is relatively more hypoxic.…”

The Lymphatic Endothelium in the Context of Radioimmuno-Oncology

“…For example, there are instances in which fractionated RT augments vessel permeability for extended periods by incremented ZO-1 and ICAM-1 expression on the endothelial surface [126]. Recent research points to high linear transfer energy (LET), such as neutron transfer, to present less pro-fibrotic and more pro-immunogenic properties than gamma ray-and X-ray-based RT approaches [127].…”