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

Authors
Nam, Jae-KyungKim, Ji-HeePark, Min-SikKim, Eun HoKim, JoonLee, Yoon-Jin
Issue Date
10월-2021
Publisher
MDPI
Keywords
X-ray radiation therapy; anti-tumor immune response; fibrotic tumor microenvironment; high linear energy transfer; neutron radiation therapy; programmed death-ligand 1
Citation
CANCERS, v.13, no.20
Indexed
SCIE
SCOPUS
Journal Title
CANCERS
Volume
13
Number
20
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/136205
DOI
10.3390/cancers13205232
ISSN
2072-6694
Abstract
Simple Summary:& nbsp;Radiation therapy can modulate anti-tumor immune responses. In this study, we investigated the relationship between the anti-tumor immune response and tumor fibrosis after X-ray or neutron radiation therapy. Neutron radiation therapy resulted in lesser fibrosis and greater anti-tumor immunity compared to X-ray irradiation. Radiation therapy-induced fibrotic changes within the tumor environment and tumor regrowth were suppressed by specifically deleting Trp53 in endothelial cells. In particular, the upregulation of PD-L1 expression after X-ray radiation therapy was significantly suppressed via EC-Trp53 deletion. Understanding the effects of different radiation therapy types on the tumor microenvironment provides strategies for enhancing the efficacy of combined radio- and immunotherapy.</p> & nbsp;</p> 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.</p>
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