Hepatoblastoma Cancer Stem Cells Express PD-L1, Reveal Plasticity and Can Emerge upon Chemotherapy

SIMPLE SUMMARY: Cancer stem cells are thought to cause a poor response to chemotherapies. The aim of our study was to explore the still unknown biology of hepatoblastoma cancer stem cells that are essential for tumorigenesis. With our investigations, we aimed to gain more insight into cancer stem cell characteristics and to provide directions for new therapeutic approaches to treat refractory hepatoblastoma. We showed that hepatoblastoma cancer stem cells express PD-L1, a factor which helps tumors escape immune attacks. Furthermore, we detected cancer stem cell progeny evolving from non-cancer stem cells. Finally, we revealed that another subset of cancer stem cells is induced during chemotherapy. Our findings give a possible explanation why chemotherapies fail in certain hepatoblastoma cases and why new therapeutic approaches should consider the plasticity of hepatoblastoma cancer stem cells. ABSTRACT: The biology of cancer stem cells (CSCs) of pediatric cancers, such as hepatoblastoma, is sparsely explored. This is mainly due to the very immature nature of these tumors, which complicates the distinction of CSCs from the other tumor cells. Previously, we identified a CSC population in hepatoblastoma cell lines expressing the CSC markers CD34 and CD90, cell surface Vimentin (csVimentin) and binding of OV-6. In this study, we detected the co-expression of the immune escape factor PD-L1 in the CSC population, whereas the other tumor cells remained negative. FACS data revealed that non-CSCs give rise to CSCs, reflecting plasticity of CSCs and non-CSCs in hepatoblastoma as seen in other tumors. When we treated cells with cisplatin and decitabine, a new CD34(+/low)OV-6(low)CD90(+) population emerged that lacked csVimentin and PD-L1 expression. Expression analyses showed that this new CSC subset shared similar pluripotency and EMT features with the already-known CSCs. FACS results further revealed that this subset is also generated from non-CSCs. In conclusion, we showed that hepatoblastoma CSCs express PD-L1 and that the biology of hepatoblastoma CSCs is of a plastic nature. Chemotherapeutic treatment leads to another CSC subset, which is highly chemoresistant and could be responsible for a poor prognosis after postoperative chemotherapy.