Presence of onco-fetal neighborhoods in hepatocellular carcinoma is associated with relapse and response to immunotherapy

期刊论文
发表日期：

2024年1月2日

查看全文

Ziyi Li,
Rhea Pai,
Saurabh Gupta,
Jennifer Currenti,
Wei Guo,
Anna Di Bartolomeo,
Hao Feng,
Zijie Zhang,
Zhizhen Li,
Longqi Liu,
Abhishek Singh,
Yinqi Bai,
Bicheng Yang,
Archita Mishra,
Katharine Yang,
Liang Qiao,
Michael Wallace,
Yujia Yin,
Qiang Xia,
Jerry Kok Yen Chan,
Jacob George,
Pierce Kah-Hoe 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 T_reg 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.