Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, China.
Guangxi Medical University cancer hospital, China.
Brief Bioinform. 2021 Sep 2;22(5). doi: 10.1093/bib/bbab130.
Targeting tumor microenvironment (TME), such as immune checkpoint blockade (ICB), has achieved increased overall response rates in many advanced cancers, such as non-small cell lung cancer (NSCLC), however, only in a fraction of patients. To improve the overall and durable response rates, combining other therapeutics, such as natural products, with ICB therapy is under investigation. Unfortunately, due to the lack of systematic methods to characterize the relationship between TME and ICB, development of rational immune-combination therapy is a critical challenge. Here, we proposed a systems pharmacology strategy to identify resistance regulators of PD-1/PD-L1 blockade and develop its combinatorial drug by integrating multidimensional omics and pharmacological methods. First, a high-resolution TME cell atlas was inferred from bulk sequencing data by referring to a high-resolution single-cell data and was used to predict potential resistance regulators of PD-1/PD-L1 blockade through TME stratification analysis. Second, to explore the drug targeting the resistance regulator, we carried out the large-scale target fishing and the network analysis between multi-target drug and the resistance regulator. Finally, we predicted and verified that oxymatrine significantly enhances the infiltration of CD8+ T cells into TME and is a powerful combination agent to enhance the therapeutic effect of anti-PD-L1 in a mouse model of lung adenocarcinoma. Overall, the systems pharmacology strategy offers a paradigm to identify combinatorial drugs for ICB therapy with a systems biology perspective of drug-target-pathway-TME phenotype-ICB combination.
靶向肿瘤微环境（TME），如免疫检查点阻断（ICB），已在许多晚期癌症中提高了总体反应率，如非小细胞肺癌（NSCLC），但仅在一部分患者中。为了提高总体和持久的反应率，正在研究将其他治疗方法，如天然产物，与 ICB 治疗相结合。不幸的是，由于缺乏系统的方法来描述 TME 和 ICB 之间的关系，因此开发合理的免疫联合治疗是一个关键挑战。在这里，我们提出了一种系统药理学策略，通过整合多维组学和药理学方法，来识别 PD-1/PD-L1 阻断的耐药调节剂，并开发其组合药物。首先，通过 TME 分层分析，从大容量测序数据中参考高分辨率单细胞数据推断出高分辨率的 TME 细胞图谱，并用于预测 PD-1/PD-L1 阻断的潜在耐药调节剂。其次，为了探索针对耐药调节剂的药物，我们进行了大规模的靶标钓取和多靶标药物与耐药调节剂之间的网络分析。最后，我们预测并验证了苦参碱能显著增强 CD8+T 细胞浸润到 TME 中，并能增强抗 PD-L1 在肺腺癌小鼠模型中的治疗效果，是一种强大的联合药物。总的来说，该系统药理学策略提供了一种从药物靶标-通路-TME 表型-ICB 组合的系统生物学角度来识别 ICB 治疗组合药物的范例。
