Jia et al. developed the tumor immune microenvironment spatial (TIMES) score, integrating the spatial expression of five biomarkers (SPON2, ZFP36L2, ZFP36, VIM, HLA-DRB1) to predict HCC recurrence risk. They identified NK cell distribution patterns in 61 patients, and validated the TIMES score as superior to standard risk stratification tools in 231 patients across five cohorts. In non-recurrent cases, SPON2+ NK cells localized to the tumor center and showed higher activation and cytotoxic marker expression. Knockout of SPON2 in NK cells reduced immune infiltration and IFNγ production in NK and CD8+ T cells, and accelerated HCC tumor growth.
Contributed by Shishir Pant
ABSTRACT: Given the high recurrence rates of hepatocellular carcinoma (HCC) post-resection(1-3), improved early identification of patients at high risk for post-resection recurrence would help to improve patient outcomes and prioritize healthcare resources(4-6). Here we observed a spatial and HCC recurrence-associated distribution of natural killer (NK) cells in the invasive front and tumour centre from 61 patients. Using extreme gradient boosting and inverse-variance weighting, we developed the tumour immune microenvironment spatial (TIMES) score based on the spatial expression patterns of five biomarkers (SPON2, ZFP36L2, ZFP36, VIM and HLA-DRB1) to predict HCC recurrence risk. The TIMES score (hazard ratio_=_88.2, P_<_0.001) outperformed current standard tools for patient risk stratification including the TNM and BCLC systems. We validated the model in 231 patients from five multicentred cohorts, achieving a real-world accuracy of 82.2% and specificity of 85.7%. The predictive power of these biomarkers emerged through the integration of their spatial distributions, rather than individual marker expression levels alone. In vivo models, including NK cell-specific Spon2-knockout mice, revealed that SPON2 enhances IFN_ secretion and NK cell infiltration at the invasive front. Our study introduces TIMES, a publicly accessible tool for predicting HCC recurrence risk, offering insights into its potential to inform treatment decisions for early-stage HCC.
Author Info: (1) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The
Author Info: (1) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China. (2) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (3) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (4) Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Singapore. (5) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (6) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (7) Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Singapore. (8) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (9) Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Singapore. (10) Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China. (11) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (12) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Duke-NUS Medical School, Singapore, Singapore. (13) Duke-NUS Medical School, Singapore, Singapore. (14) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (15) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (16) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (17) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. (18) Hunan Cancer Hospital, The Affiliated Cancer Hospital of Central South University, Changsha, China. (19) State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Fudan University, Shanghai, China. (20) Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Singapore. yeongps@imcb.a-star.edu.sg. Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore. yeongps@imcb.a-star.edu.sg. Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Singapore, Singapore. yeongps@imcb.a-star.edu.sg. Cancer Science Institute, National University of Singapore, Singapore, Singapore. yeongps@imcb.a-star.edu.sg. (21) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. liulx@ustc.edu.cn. (22) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. charless@ustc.edu.cn. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. charless@ustc.edu.cn.
