Qiu et al. established a detailed spatial map of single-cell phenotypes and multicellular neighborhoods of tumor tissues from 401 patients with hepatocellular carcinoma. The spatial single-cell analysis identified three spatial patterns (SP-HI, -LI, and -PF) with distinct prognostic, genomic, and molecular features. An integrated analysis combining CODEX, scRNAseq, and spatial transcriptomics datasets identified that co-localization of VIMhigh macrophages and Tregs correlated with tumor progression in HCC. In vitro functional studies showed that VIMhigh macrophages secreted IL-1β to promote the immune-suppressive function of Tregs.
Contributed by Shishir Pant
ABSTRACT: Tumor microenvironment heterogeneity in hepatocellular carcinoma (HCC) on a spatial single-cell resolution is unclear. Here, we conducted co-detection by indexing to profile the spatial heterogeneity of 401 HCC samples with 36 biomarkers. By parsing the spatial tumor ecosystem of liver cancer, we identified spatial patterns with distinct prognosis and genomic and molecular features, and unveiled the progressive role of vimentin (VIM)(high) macrophages. Integration analysis with eight independent cohorts demonstrated that the spatial co-occurrence of VIM(high) macrophages and regulatory T cells promotes tumor progression and favors immunotherapy. Functional studies further demonstrated that VIM(high) macrophages enhance the immune-suppressive activity of regulatory T cells by mechanistically increasing the secretion of interleukin-1_. Our data provide deep insights into the heterogeneity of tumor microenvironment architecture and unveil the critical role of VIM(high) macrophages during HCC progression, which holds potential for personalized cancer prevention and drug discovery and reinforces the need to resolve spatial-informed features for cancer treatment.
Author Info: (1) Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. National Center for Liver Cancer, Shanghai, China.
Author Info: (1) Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. National Center for Liver Cancer, Shanghai, China. (2) National Center for Liver Cancer, Shanghai, China. The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China. (3) Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China. (4) Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China. (5) Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (6) Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China. (7) Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. (8) National Center for Liver Cancer, Shanghai, China. The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China. (9) Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China. (10) National Center for Liver Cancer, Shanghai, China. The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China. (11) Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. hywangk@vip.sina.com. The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China. hywangk@vip.sina.com. Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China. hywangk@vip.sina.com. Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, China. hywangk@vip.sina.com. Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China. hywangk@vip.sina.com. (12) Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. chenlei@smmu.edu.cn. National Center for Liver Cancer, Shanghai, China. chenlei@smmu.edu.cn. The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China. chenlei@smmu.edu.cn. Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, China. chenlei@smmu.edu.cn. Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China. chenlei@smmu.edu.cn.
