Systems pharmacology: a combination strategy for improving efficacy of PD-1/PD-L1 blockade

Author:

Zheng Chunli1,Xiao Yue1,Chen Chuang2,Zhu Jinglin1,Yang Ruijie1,Yan Jiangna1,Huang Ruifei1,Xiao Wei3,Wang Yonghua4,Huang Chao5

Affiliation:

1. Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, China

2. Guangxi Medical University cancer hospital, China

3. State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Kanion Pharmaceutical Co. Ltd, China

4. Center of Bioinformatics, College of Life Sciences,Northwest A&F University and at Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, China

5. Center of Bioinformatics, College of Life Sciences, Northwest A&F University and at Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, China

Abstract

Abstract 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.

Funder

National Natural Science Foundation of China

64th batch of postdoctoral general programs in China

National Science and Technology Major Project of China

Publisher

Oxford University Press (OUP)

Subject

Molecular Biology,Information Systems

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