A Novel Humanized Immune Stroma PDX Model for Therapeutic Studies

Standard preclinical human tumor models lack a human tumor stroma. However, as stroma contributes to therapeutic resistance, the lack of human stroma may make current models less stringent for testing new therapies. To address this, we created a human in mouse model of cancer with a human tumor stroma. This humanized immune stroma patient derived xenograft (HIS-PDX) uses patient-derived tumor cells, cancer-associated mesenchymal stem cells and human endothelial cells transplanted into BLT (bone marrow, liver, thymus) humanized mice. The model contains human connective tissues, vascular and immune cell infiltrates. RNA sequencing analysis demonstrated a 94-96% correlation with primary human tumor. Using this model, we demonstrate the impact of human tumor stroma on response to both small molecule and immune therapies. Combined our data confirm a critical role for human stoma plays an important role in therapeutic response and that this model can be an important tool for preclinical drug testing.