Low-dose radiation as a potential strategy for alleviating lung injury caused by radiotherapy combined with immunotherapy: A preclinical study

Background and Purpose: Radiotherapy combined with immunotherapy has been shown to improve thoracic tumor outcomes while increasing the risk of lung injury. Low-dose radiotherapy (LD-RT) has been proven efficient in managing inflammatory diseases. This study aims to investigate whether LD-RT might alleviate lung injury induced by radiotherapy combined with immunotherapy, and attempt to explore its underlying mechanisms thereby offering novel insights for clinical application. Methods: To establish a mouse model of lung injury caused by radiotherapy combined with immunotherapy, C57 BL/6J mice received intraperitoneal injections of programmed death 1(PD-1) inhibitor weekly and a single dose of 15 Gy whole thoracic irradiation. Then they received a single dose of LD-RT at 1.0 Gy or 1.5 Gy on Day 14 or 28. The mice were euthanized on Day 42, and lung tissue samples were collected for HE, Masson's trichrome, and immunohistochemical staining to evaluate lung tissue damage, fibrosis, and lymphocyte infiltration. The expression levels of cytokine were quantified by the enzyme-linked immunosorbent assay. Results: Both low-dose of 1.0 Gy and 1.5 Gy attenuated lung injury caused by radiotherapy combined with PD-1 inhibitors, but 1.5 Gy was more effective. Compared with Day 14, LD-RT at 1.5 Gy on Day 28 was more effective in alleviating alveolar inflammation and reducing collagen deposition, and inhibiting lymphocyte infiltration and secretion of inflammatory cytokine in lung tissue. Conclusion: Low-dose radiation alleviated lung injury caused by radiotherapy combined with PD-1 inhibitor, and the alleviating effect is closely related to the timing and dose of the radiotherapy administered.