Alleviating lung injury and pulmonary fibrosis in radiotherapy-immunotherapy combination: The role of low-dose radiation therapy.

Abstract

e14632 Background: Lung cancer continues to be the primary cause of cancer-related mortality on a global scale. The integration of radiotherapy and immunotherapy has yielded significant advancements in the treatment of locally advanced non-small cell lung cancer. However, the occurrence of treatment-associated pneumonia remains the predominant adverse event necessitating treatment cessation and permanent medication discontinuation. The immune-modulating effects of radiation therapy on the body contribute to a complex interplay between radiation and inflammation. Low-dose radiotherapy (LD-RT) has historically been utilized for the management of benign inflammatory conditions. Recently, LD-RT was found to be effective in treating severe pneumonia in patients with severe COVID-19 as well as acute respiratory distress syndrome (ARDS). This investigation seeks to examine the impact of LD-RT on lung tissue morphology and the inflammatory immune microenvironment in preclinical models of lung injury induced by high-dose radiotherapy combined with programmed death-1(PD-1) inhibitor therapy. Methods: 6-8 week old C57BL/6 mice were treated with a single high-dose thoracic radiotherapy (15Gy) and the PD-1 inhibitor (once a week), with or without the low-dose radiotherapy (1.0/1.5Gy) four weeks later. Lung tissue was collected one and a half months and three months respectively after the initial high-dose radiotherapy for evaluation using HE and Masson staining, Image J software for analysis of collagen volume fraction (CVF), and immunohistochemical staining for CD3+ and CD8+ T lymphocytes. Cytokine transforming growth factor (TGF)-β1、interleukin (IL)-6 and tumor necrosis factor (TNF)-α level in lung tissue was detected by ELISA. Statistical analysis was performed using GraphPad Prism 9.5.0 software. Results: The radiotherapy-immunotherapy combination (iRT) group exhibits notable lung injury characterized by the proliferation of alveolar type II epithelial cells, thickening of alveolar septa, interstitial edema, pulmonary congestion and bleeding, increased infiltration of inflammatory cells, and significant deposition of interstitial collagen fibers. In contrast, the iRT+ LD-RT group demonstrates a significant decrease in lung tissue damage, interstitial fibrosis, collagen volume fraction (CVF), levels of IL-6 and TGF-β, as well as the infiltration of CD3+ and CD8+T cells compared to the iRT group. Conclusions: Low-dose radiation has the potential to ameliorate lung injury induced by the combination of radiotherapy and PD-1 inhibitors by modulating the inflammatory milieu, thereby potentially mitigating the development of pulmonary fibrosis.