Single-cell RNA sequencing reveals the suppressive effect of PPP1R15A inhibitor Sephin1 in antitumor immunity
Rongjing Wang,
Yuchao Zhang,
Shiwei Guo,
Siyu Pei,
Wei Guo,
Zhenchuan Wu,
Hailong Wang,
Minghui Wang,
Yizhe Li,
Yufei Zhu,
Ling-Hua Meng,
Jingyu Lang,
Gang Jin,
Yichuan Xiao,
Landian Hu,
Xiangyin Kong
Affiliations
Rongjing Wang
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai, China
Yuchao Zhang
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai, China
Shiwei Guo
Changhai Hospital, Department of Hepatobiliary Pancreatic Surgery, Shanghai, China
Siyu Pei
Department of Thoracic Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200030, China
Wei Guo
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai, China
Zhenchuan Wu
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai, China; University of Chinese Academy of Sciences, Shanghai, China
Hailong Wang
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai, China; ShanghaiTech University, School of Life Science and Technology, Shanghai, China
Minghui Wang
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai, China; University of Chinese Academy of Sciences, Shanghai, China
Yizhe Li
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai, China; University of Chinese Academy of Sciences, Shanghai, China
Yufei Zhu
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai, China
Ling-Hua Meng
Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Jingyu Lang
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai, China
Gang Jin
Changhai Hospital, Department of Hepatobiliary Pancreatic Surgery, Shanghai, China; Corresponding author
Yichuan Xiao
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai, China; Corresponding author
Landian Hu
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai, China; Anda Biology Medicine Development (Shenzhen) Co, Ltd, Shanghai, China; Corresponding author
Xiangyin Kong
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai, China; Corresponding author
Summary: Protein phosphatase 1 regulatory subunit 15A (PPP1R15A) is an important factor in the integrated stress response (ISR) in mammals and may play a crucial role in tumorigenesis. In our studies, we found an inhibitor of PPP1R15A, Sephin1, plays a protumorigenic role in mouse tumor models. By analyzing the single-cell transcriptome data of the mouse tumor models, we found that in C57BL/6 mice, Sephin1 treatment could lead to higher levels of ISR activity and lower levels of antitumor immune activities. Specifically, Sephin1 treatment caused reductions in antitumor immune cell types and lower expression levels of cytotoxicity-related genes. In addition, T cell receptor (TCR) repertoire analysis demonstrated that the clonal expansion of tumor-specific T cells was inhibited by Sephin1. A special TCR + macrophage subtype in tumor was identified to be significantly depleted upon Sephin1 treatment, implying its key antitumor role. These results suggest that PPP1R15A has the potential to be an effective target for tumor therapy.
