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

doi:10.1016/j.isci.2023.105954

Single-cell RNA sequencing reveals the suppressive effect of PPP1R15A inhibitor Sephin1 in antitumor immunity

iScience. 2023 Jan 13;26(2):105954. doi: 10.1016/j.isci.2023.105954. eCollection 2023 Feb 17.

Authors

Rongjing Wang¹, Yuchao Zhang¹, Shiwei Guo², Siyu Pei³, Wei Guo¹, Zhenchuan Wu^{1

4}, Hailong Wang^{1

5}, Minghui Wang^{1

4}, Yizhe Li^{1

4}, Yufei Zhu¹, Ling-Hua Meng⁶, Jingyu Lang¹, Gang Jin², Yichuan Xiao¹, Landian Hu^{1

7}, Xiangyin Kong¹

Affiliations

¹ Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai, China.
² Changhai Hospital, Department of Hepatobiliary Pancreatic Surgery, Shanghai, China.
³ Department of Thoracic Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200030, China.
⁴ University of Chinese Academy of Sciences, Shanghai, China.
⁵ ShanghaiTech University, School of Life Science and Technology, Shanghai, China.
⁶ Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁷ Anda Biology Medicine Development (Shenzhen) Co, Ltd, Shanghai, China.

Abstract

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.

Keywords: Biological sciences; Immunology; Molecular biology; Transcriptomics.