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

Jae-Kyung Nam,Joon Kim,Min-Sik Park,Yoon-Jin Lee,Ji-Hee Kim,Eun Ho Kim

doi:10.3390/cancers13205232

Abstract

Simple SummaryRadiation 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. 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.

Highlights

Unlike low linear energy transfer (LET) radiation, which relies on the generation of reactive oxygen species for cytotoxicity, neutron radiation therapy does not depend on the presence of oxygen, and cellular damage is primarily mediated via nuclear interactions
We previously reported that X-ray radiation-induced endothelial-to-mesenchymal transition (EndMT) enhanced vascular fibrosis and collagen deposition, especially around tumor vessels within the tumor microenvironment (TME)
To explore the effects of neutron irradiation on the TME, we examined tumor regrowth, collagen deposition, and EndMT after radiation therapy in EC-p53KO mice (Figures 1 and 2)

Summary

Introduction

Radiation therapy with high linear energy transfer (LET) radiation (alpha particles, protons, or neutrons) is more effective at killing tumor cells than low LET radiation, such as X-rays and γ-rays [1,2,3]. Unlike low LET radiation, which relies on the generation of reactive oxygen species for cytotoxicity, neutron radiation therapy does not depend on the presence of oxygen, and cellular damage is primarily mediated via nuclear interactions. The differences between the effects of low LET and high LET within the tumor microenvironment (TME) remain unclear [4,5]. Radiation therapy modulates the anti-tumor immune response [6,7]. Combinations of immune checkpoint blockade via antibodies against programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) with radiotherapy have been explored in the clinic [8]

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