作者
Ziyi Li,Rhea Pai,Saurabh Gupta,Jennifer Currenti,Wei Guo,Anna Di Bartolomeo,Hao Feng,Zi-Jie Zhang,Zhizhen Li,Longqi Liu,Abhishek Singh,Yinqi Bai,Bicheng Yang,Archita Mishra,Katharine Yang,Liang Qiao,M. Christopher Wallace,Yujia Yin,Qiang Xia,Jerry Kok Yen Chan,Jacob George,Pierce K. H. Chow,Florent Ginhoux,Ankur Sharma
摘要
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. Ginhoux and colleagues perform multi-omic characterization of hepatocellular carcinoma and identify an onco-fetal niche that includes fibroblasts, macrophages and endothelial cells and influences immunotherapy response and relapse.