Tang et al. used single-cell spatial transcriptomics to comprehensively profile tertiary lymphoid structures (TLSs) under various maturation stages in hepatocellular carcinoma (HCC). Immature TLSs were classified as conforming or deviating, exhibiting distinct molecular features and response to ICB therapy. Conforming TLSs, like mature TLSs, were associated with response to ICB. Tumor cell-driven tryptophan metabolism in the TME influenced the deviation of TLS maturation. Inhibiting tryptophan metabolism promoted intratumoral TLS maturation, enhanced tumor control, and synergized with anti-PD-1 therapy in an orthotopic HCC mouse model.
Contributed by Shishir Pant
ABSTRACT: Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates found in numerous cancers, often linked to enhanced immunotherapy responses and better clinical outcomes. However, the factors driving TLS maturation are not fully understood. Using near single-cell spatial transcriptomic mapping, we comprehensively profile TLSs under various maturation stages and their microenvironment in hepatocellular carcinoma (HCC). Based on their developmental trajectories, we classify immature TLSs into two groups: conforming and deviating TLSs. Our findings indicate that conforming TLSs, similar to mature TLSs, possess a niche function for immunotherapy responses, while deviating TLSs do not. We discover that the tryptophan-enriched metabolic microenvironment shaped by malignant cells contributes to the deviation of TLS maturation. Inhibiting tryptophan metabolism promotes intratumoral TLS maturation and enhances tumor control, synergizing with anti-PD-1 treatments. Therefore, promoting TLS maturation represents a potential strategy to improve antitumor responses and immunotherapy outcomes.
Author Info: (1) Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Zhongshan School of Medicine,
Author Info: (1) Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: tangzhh99@mail.sysu.edu.cn. (2) BGI Research, Sanya 572025, China; BGI Research, Hangzhou 310030, China. (3) BGI Research, Hangzhou 310030, China. (4) Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. (5) Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (6) Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (7) Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (8) Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (9) Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (10) BGI Research, Chongqing 401329, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. (11) BGI Research, Sanya 572025, China; BGI Research, Hangzhou 310030, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. (12) BGI Research, Sanya 572025, China; BGI Research, Hangzhou 310030, China; BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450000, China. (13) BGI Research, Sanya 572025, China; BGI Research, Hangzhou 310030, China. (14) Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. (15) Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. (16) Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (17) Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, 80336 Munich, Germany. (18) Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (19) BGI Research, Hangzhou 310030, China; Shenzhen Bay Laboratory, Shenzhen 518000, China; Shenzhen Key Laboratory of Single-Cell Omics, BGI-Shenzhen, Shenzhen 518120, China; The Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, Guangzhou 510000, China. Electronic address: liushiping@genomics.cn. (20) Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Clinical Trial Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: pengsui@mail.sysu.edu.cn. (21) Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: kuangm@mail.sysu.edu.cn.
