Liu Shilong, Liu Lili, Ma Jianli, Li Jian, Wang Liqun, Xu Jianyu, Hu Songliu
Department of Radiation Oncology, Harbin Medical University Cancer Hospital Harbin 150081, Heilongjiang, China.
Am J Cancer Res. 2024 Jun 15;14(6):2881-2893. doi: 10.62347/WDOC4830. eCollection 2024.
Radiotherapy (RT) is essential in the treatment of thoracic neoplasms. Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have significantly improved the clinical management of non-small cell lung carcinoma (NSCLC).
This study aimed to investigate the impact of combining anti-PD-1 (αPD-1) immunotherapy with radiotherapy on lung injury. Additionally, it investigates the role and mechanism of interleukin (IL)-17A, a pro-inflammatory cytokine involved in immune regulation, in lung injury arising from this combination treatment.
Experiments were conducted using a PD-1 deficient mouse model to simulate acute radiation-induced lung injury. Inbred female BALB/c wild-type (WT) mice and PD-1 mice were divided into six groups: WT group, PD-1 group, WT_LIR + IgG group, PD-1_LIR + IgG group, WT_LIR + αIL-17A group, and PD-1_LIR + αIL-17A group. The mice were subjected to 8 Gy × 3 irradiation in both lungs. Various methods including histological scoring, immunofluorescence, qPCR, and flow cytometry were employed to analyze the role of IL-17A in lung injury and the effect of PD-1 gene deletion on the severity of radiation-induced lung injury.
The PD-1_LIR mice exhibited evident radiation-induced lung injury after receiving 8 Gy × 3 doses in both lungs. The expression level of IL-17A peaked at 2 weeks. Lung injury-related factors IFN-γ, TNF-α, IL-6, and RORγt in the PD-1_LIR groups increased 2 weeks after irradiation. The CD4 and CD8 T cells in lung tissue of the PD-1_LIR mice significantly increased. Post αIL-17A administration, the incidence of alveolitis in the treatment group decreased, the expression levels of lung injury-related factors IFN-γ, TNF-α, IL-6, RORγt, TGF-β1, and IL-17A decreased, and the CD4 and CD8 T cells in lung tissue significantly declined. Throughout the observation period, the survival rate of the mice in the treatment group was significantly higher than that of the isotype control group (60% vs 0%, P = 0.011).
Combining αPD-1 immunotherapy with radiotherapy in mice can induce radiation-induced lung injury, with IL-17A playing a critical role in this process. αIL-17A administration significantly mitigated radiation-induced lung injury caused by the combination of αPD-1 immunotherapy and radiotherapy, improving mouse survival. This finding offers a promising treatment target for lung injury resulting from the combination of αPD-1 immunotherapy and radiotherapy.
放射治疗（RT）在胸部肿瘤的治疗中至关重要。靶向程序性细胞死亡蛋白1（PD-1）和程序性死亡配体1（PD-L1）的免疫检查点抑制剂显著改善了非小细胞肺癌（NSCLC）的临床治疗。
本研究旨在探讨抗PD-1（αPD-1）免疫疗法与放射治疗联合应用对肺损伤的影响。此外，研究参与免疫调节的促炎细胞因子白细胞介素（IL）-17A在这种联合治疗引起的肺损伤中的作用和机制。
使用PD-1缺陷小鼠模型进行实验，以模拟急性辐射诱导的肺损伤。将近交系雌性BALB/c野生型（WT）小鼠和PD-1小鼠分为六组：WT组、PD-1组、WT_LIR + IgG组、PD-1_LIR + IgG组、WT_LIR + αIL-17A组和PD-1_LIR + αIL-17A组。对小鼠双肺进行8 Gy×3照射。采用组织学评分、免疫荧光、qPCR和流式细胞术等多种方法分析IL-17A在肺损伤中的作用以及PD-1基因缺失对辐射诱导肺损伤严重程度的影响。
PD-1_LIR小鼠双肺接受8 Gy×3剂量照射后出现明显的辐射诱导肺损伤。IL-17A的表达水平在2周时达到峰值。照射后2周，PD-1_LIR组中与肺损伤相关的因子IFN-γ、TNF-α、IL-6和RORγt增加。PD-1_LIR小鼠肺组织中的CD4和CD8 T细胞显著增加。给予αIL-17A后，治疗组的肺泡炎发生率降低，与肺损伤相关的因子IFN-γ、TNF-α、IL-6、RORγt、TGF-β1和IL-17A的表达水平降低，肺组织中的CD4和CD8 T细胞显著减少。在整个观察期内，治疗组小鼠的存活率显著高于同型对照组（60%对0%，P = 0.011）。
在小鼠中，αPD-1免疫疗法与放射治疗联合应用可诱导辐射诱导肺损伤，IL-17A在此过程中起关键作用。给予αIL-17A可显著减轻αPD-1免疫疗法与放射治疗联合引起的辐射诱导肺损伤，提高小鼠存活率。这一发现为αPD-1免疫疗法与放射治疗联合导致肺损伤提供了一个有前景的治疗靶点。
