Liu et al. generated a time-resolved scRNAseq map of the immune dynamic during human lung adenocarcinoma development from initiation through invasion, and found that while NK cells reduced, CD4+ T cells, germinal center B cells, and dysfunctional CD8+ T cells accumulated and formed tertiary lymphoid structures (TLSs), which were associated with patient outcomes. Functional studies showed that CD4+ T cells aggregated, CXCL13-expressing Tfh cells were generated, and then B cells accumulated, resulting in TLS formation. The antitumor effects of TLSs required Tfh and B cells, and were likely mediated through IL-21–IL-21R signaling.
Contributed by Lauren Hitchings
ABSTRACT: The immune responses during the initiation and invasion stages of human lung adenocarcinoma (LUAD) development are largely unknown. Here, we generated a single-cell RNA sequencing map to decipher the immune dynamics during human LUAD development. We found that T follicular helper (Tfh)-like cells, germinal center B cells, and dysfunctional CD8(+) T cells increase during tumor initiation/invasion and form a tertiary lymphoid structure (TLS) inside the tumor. This TLS starts with an aggregation of CD4(+) T cells and the generation of CXCL13-expressing Tfh-like cells, followed by an accumulation of B cells, and then forms a CD4(+) T and B cell aggregate. TLS and its associated cells are correlated with better patient survival. Inhibiting TLS formation by Tfh or B cell depletion promotes tumor growth in mouse models. The anti-tumoral effect of the Tfh-dependent TLS is mediated through interleukin-21 (IL-21)-IL-21 receptor signaling. Our study establishes an anti-tumoral role of the Tfh-dependent TLS in the development of LUAD.
Author Info: (1) Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518
Author Info: (1) Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen Zhongshan Obstetrics & Gynecology Hospital, Shenzhen, China. (2) Department of Immunology, School of Basic Medical Sciences, Wuxi Medical Center, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing 211166, Jiangsu, China; School of Chemistry and Chemical Engineering, Southeast University, Nanjing, China. (3) State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. (4) Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. (5) Department of Pathology, Harbin Medical University, Harbin, China. (6) Department of Automation, Xiamen University, Xiamen, Fujian, China. (7) Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. (8) Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen Zhongshan Obstetrics & Gynecology Hospital, Shenzhen, China; Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-implantation, Shenzhen, Guangdong, China. (9) Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen Zhongshan Obstetrics & Gynecology Hospital, Shenzhen, China; Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-implantation, Shenzhen, Guangdong, China. (10) State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. (11) Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. (12) Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. (13) School of Medicine, Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, China. (14) Department of Immunology, School of Basic Medical Sciences, Wuxi Medical Center, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing 211166, Jiangsu, China. Electronic address: chenyun@njmu.edu.cn. (15) The Department of Thoracic Surgery, Shenzhen Institute of Respiratory Disease, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China. Electronic address: wang.guangsuo@szhospital.com. (16) Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: changchenc@tongji.edu.cn. (17) Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. Electronic address: hj.li@siat.ac.cn.
