Y. Mo1,2, M. Wu2, D. Chen2, and J. Yu1,2; 1The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China, 2Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
Purpose/Objective(s): Immune checkpoint blockade (ICB) combined with radiotherapy(RT) have increased survival for patients, but also bring adverse effects. Herein, integration of real-world data, genomics, transcriptome analysis and mouse model were performed to identify the role of programmed cell death ligand-1(PDL-1) in radiation induced lung injury (RILI) and investigate drug interactions which offered targets for clinical intervention. Materials/
Methods: We fully utilize the FDA Adverse Event Reporting System(FAERS) to analyze the interaction of ICB and RT in pulmonary toxicity through disproportionality analysis. Mouse models were established based on evaluation of histopathological characteristics, micro–computed tomography and lung injury biomarkers. We investigated the PDL-1 role of collagen deposition in RILI. Genomewide association studies(GWAS) and transcriptome analysis were performed to illustrate the role of PDL-1 in interstitial lung disease (ILD), followed by mendelian randomization (MR) analysis to identify drug targets, and finally validated drug-targets with clinical data from non-small cell lung cancer (NSCLC) patients with pulmonary toxicity. Results: ICB combined with RT was at the highest risk of pulmonary toxicity. The ROR for interaction effect between ICB and RT was 3.727(95% CI, 2.256-6.150, P<0.01), Anti-PD-L1 posed greater risk of pulmonary toxicity than anti-PD-1 and anti-CTLA-4 (anti-PDL-1 vs anti-PD-1: HR=9.355; anti-PDL-1 vs anti-CTLA-4: HR=6.985). A correlation relationship between CD274 mRNA and ILD was identified. Cell-specific(CD4+T cell, CD8+ T cell and CD31+ cell) PDL-1 in progression of RILI were found to be associated with collagen deposition. Notably, analysis of concomitant medications revealed that thyroxine was a protective factor (HR=0.190, 95% CI: 0.068-0.534, P</i>=0.002) for patients received ICB-RT. Thyroid hormone receptor alpha (rs359829347, rs9896694, rs7502912, rs17678694) and thyroid hormone receptor beta (rs9310737, rs2135147, rs1399702292, rs4858593) were identified as drug targets. Moreover, MR analysis suggested that hypothyroidism showed a negative effect on ILD(OR=1.223, 95% CI:1.042-1.434, P=0.016). Lastly, clinical data indicated that FT3/FT4 levels were positively correlated with the interval between treatment and ILD (FT3 and ILD: R=0.751, P<0.001; FT4 and ILD: R=0.642, P=0.004). Conclusion: Interaction effect of ICB and RT increased the risk of pulmonary toxicity with anti-PDL-1 significantly at risk compared to anti-PD-1 and anti-CTLA-4. The cir-eQTL of CD274 in ILD, PDL-1 expression of endothelial cells, CD4+ T cells and CD8+ T cells in irradiated lungs may explain the effect. Notably, thyroid hormone receptor was identified as drug targets for pulmonary toxicity. And thyroxine ameliorated pulmonary toxicity in NSCLC patients received ICB-RT combination therapy. The identification of PDL-1 and thyroxine provided a new insight to investigate RILI.
