SUMMARYPluripotent stem cell (PSC)-derived hepatocyte-like cells (HLC) have shown great potential as an alternative to primary human hepatocytes (PHH) for in vitro modeling. Several differentiation protocols have been described to direct PSC towards the hepatic fate, although the resulting HLC have shown more a fetal than adult phenotype. Here, by leveraging recent knowledge of the signaling pathways involved in liver development, we describe a robust, scalable protocol that allows to consistently generate high-quality HLC from both ESC and iPSC. Such HLC are comparable to adult PHH in terms of key mature liver functions and proved suitable to assess drug hepatotoxicity, as a proof of concept of their potential as a physiologically representative alternative for in vitro modeling.
Modeling the tumor-immune cell interactions in humanized mice is complex and limits drug development. Here, we generated easily accessible tumor models by transforming either primary skin fibroblasts or iPSC-derived cell lines injected in immune-deficient mice reconstituted with human autologous immune cells. Our results showed that either fibroblastic, hepatic or neural tumors were all efficiently infiltrated and partially or totally rejected by autologous immune cells in humanized mice. Characterization of tumor immune infiltrates revealed high expression levels of the dysfunction markers Tim3 and PD-1 in T cells and an enrichment in regulatory T cell suggesting rapid establishment of an immunosuppressive microenvironment. Inhibition of PD-1 by Nivolumab in humanized mice resulted in an increased immune cell infiltration and a slight decrease in tumor growth. We expect these versatile and accessible cancer models will facilitate preclinical studies and the evaluation of autologous cancer immunotherapies across a range of different tumor cell types.
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