Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, Perth, Western Australia, Australia.
Curtin Medical School, Curtin University, Perth, Western Australia, Australia.
Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia.
Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Institute of Transplantation, Shanghai, China.
Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
BGI-Shenzhen, Beishan Industrial Zone, Shenzhen, P. R. China.
BGI-Australia, Herston, Queensland, Australia.
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore.
Telethon Kids Institute, University of Western Australia, Perth Children's Hospital, Nedlands, Western Australia, Australia.
Department of Hepatology and Western Australian Liver Transplant Service, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
Medical School, University of Western Australia, Nedlands, Western Australia, Australia.
Department of Obstetrics and Gynecology, Xinhua Hospital Affiliated to Shanghai Jiaotong University Medicine School, Shanghai, China.
Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore, Singapore.
Academic Clinical Program in Obstetrics and Gynaecology, Duke-NUS Medical School, Singapore, Singapore.
Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Singapore, Singapore. pierce.chow@duke-nus.edu.sg.
Surgery Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore. pierce.chow@duke-nus.edu.sg.
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. florent_ginhoux@immunol.a-star.edu.sg.
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore. florent_ginhoux@immunol.a-star.edu.sg.
Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore. florent_ginhoux@immunol.a-star.edu.sg.
Gustave Roussy Cancer Campus, Villejuif, France. florent_ginhoux@immunol.a-star.edu.sg.
Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, Perth, Western Australia, Australia. ankur.sharma@perkins.org.au.
Curtin Medical School, Curtin University, Perth, Western Australia, Australia. ankur.sharma@perkins.org.au.
Institute of Molecular and Cell Biology, A∗STAR, Singapore, Singapore. ankur.sharma@perkins.org.au.
KK Research Centre, KK Women's and Children's Hospital, Singapore, Singapore. ankur.sharma@perkins.org.au.
Onco-fetal reprogramming of the tumor ecosystem induces fetal developmental signatures in the tumor microenvironment, leading to immunosuppressive features. Here, we employed single-cell RNA sequencing, spatial transcriptomics and bulk RNA sequencing to delineate specific cell subsets involved in hepatocellular carcinoma (HCC) relapse and response to immunotherapy. We identified POSTN+ extracellular matrix cancer-associated fibroblasts (EM CAFs) as a prominent onco-fetal interacting hub, promoting tumor progression. Cell-cell communication and spatial transcriptomics analysis revealed crosstalk and co-localization of onco-fetal cells, including POSTN+ CAFs, FOLR2+ macrophages and PLVAP+ endothelial cells. Further analyses suggest an association between onco-fetal reprogramming and epithelial-mesenchymal transition (EMT), tumor cell proliferation and recruitment of Treg cells, ultimately influencing early relapse and response to immunotherapy. In summary, our study identifies POSTN+ CAFs as part of the HCC onco-fetal niche and highlights its potential influence in EMT, relapse and immunotherapy response, paving the way for the use of onco-fetal signatures for therapeutic stratification.
