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.
Nat Cancer. 2024 Jan;5(1):167-186. doi: 10.1038/s43018-023-00672-2. Epub 2024 Jan 2.
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 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.
肿瘤生态系统的胚胎重编程诱导肿瘤微环境中出现胎儿发育特征，导致免疫抑制特征。在这里，我们采用单细胞 RNA 测序、空间转录组学和批量 RNA 测序来描绘参与肝细胞癌 (HCC) 复发和免疫治疗反应的特定细胞亚群。我们确定 POSTN 细胞外基质癌症相关成纤维细胞 (EM CAFs) 是一个突出的胚胎重编程相互作用枢纽，促进肿瘤进展。细胞间通讯和空间转录组学分析揭示了包括 POSTN CAFs、FOLR2 巨噬细胞和 PLVAP 内皮细胞在内的胚胎重编程细胞的串扰和共定位。进一步的分析表明，胚胎重编程与上皮-间充质转化 (EMT)、肿瘤细胞增殖和 T 细胞募集之间存在关联，最终影响早期复发和对免疫治疗的反应。总之，我们的研究将 POSTN CAFs 确定为 HCC 胚胎重编程生态位的一部分，并强调了其在 EMT、复发和免疫治疗反应中的潜在影响，为利用胚胎重编程特征进行治疗分层铺平了道路。
