Autologous humanized mouse models of iPSC-derived tumors allow for the evaluation and modulation of cancer-immune cell interactions

Abstract

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.

Senescence and Aging: Does It Impact Cancer Immunotherapies?

“…Whether human senescent fibroblasts, through their SASP, have positive or negative impacts on the tumor immune response is not clear at this point. To answer that question, one will need to use newly developed mouse models where tumor cells can be rejected in humanized mice [ 79 ]. While not the topic of this review, several studies have shown that cancer treatment-induced senescence has a major impact on the rejection of murine tumors by immune cells [ 80 ].…”