School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 7 Sassoon Road, Hong Kong Special Administrative Region, People's Republic of China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, People's Republic of China.
J Cancer Res Clin Oncol. 2021 Nov;147(11):3279-3288. doi: 10.1007/s00432-021-03740-1. Epub 2021 Jul 29.
PD-1/PD-L1 might have a causal role in operating lung cancer risk. However, such an association has not been investigated in the general population. We assessed whether PD-L1 has an independent effect on lung cancer risk using two-sample Mendelian randomization (MR) based on a proteomic genome-wide association study (3301 health participants) of European ancestry and the International Lung cancer Consortium (11,348 cases and 15,861 controls). Negative control analyses using chronic obstructive pulmonary disease (COPD)/asthma/interstitial lung disease (ILD)-related infection (~ 22,730 cases and ~ 112,908 controls) were also conducted to enhance the credibility of the selected instruments and MR-based estimates. This study found that genetically predicted PD-1/PD-L1 were not significantly associated with lung cancer after adjustment for multiplicity. However, suggestive evidence was observed for the total effect of higher PD-1 with decreased lung cancer risk and the direct effect (i.e., not mediated by PD-1 and smoking) of lower PD-L1 with decreased lung cancer risk. No association between genetically predicted PD-L1 and COPD/asthma/ILD related infection was noted. Taken together, our findings suggest that interventions decreasing PD-L1 might have a role in lowering lung cancer risk.
PD-1/PD-L1 可能在肺癌风险中起因果作用。然而，这种关联尚未在普通人群中进行研究。我们使用基于蛋白质组全基因组关联研究（3301 名欧洲血统的健康参与者）和国际肺癌联盟（11348 例病例和 15861 例对照）的两样本 Mendelian 随机化（MR），评估 PD-L1 是否对肺癌风险有独立影响。还使用与慢性阻塞性肺疾病（COPD）/哮喘/间质性肺疾病（ILD）相关的感染（22730 例病例和112908 例对照）进行了阴性对照分析，以增强所选工具和基于 MR 的估计的可信度。本研究发现，经过多重调整后，遗传预测的 PD-1/PD-L1 与肺癌无显著相关性。然而，对于较高的 PD-1 与降低肺癌风险的总效应以及较低的 PD-L1 与降低肺癌风险的直接效应（即不由 PD-1 和吸烟介导）观察到了提示性证据。遗传预测的 PD-L1 与 COPD/哮喘/ILD 相关感染之间没有关联。综上所述，我们的研究结果表明，降低 PD-L1 的干预措施可能在降低肺癌风险方面发挥作用。
