A novel humanized immune stroma PDX cancer model for therapeutic studies

TL;DR

A new cancer model with human tumor stroma and immune cells better predicts therapy response and shows how stroma affects immunotherapy.

Contribution

A novel HIS-PDX model incorporating human stroma and immune cells is developed to better mimic human tumor environments for drug testing.

Findings

HS-PDX models show greater resistance to therapies and better reflect patient responses compared to standard PDX models.

HIS-PDX models contain human immune and vascular components and correlate 94–96% with primary human tumors.

Human tumor stroma recruits TAMs and causes tumor immune exclusion, suppressing immunotherapy response.

Abstract

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, using patient-derived tumor cells, patient-derived cancer-associated mesenchymal stem/progenitor cells, and human endothelial cells, we created a human stroma-patient-derived xenograft (HS-PDX) tumor model. HS-PDX, compared to the standard PDX model, demonstrates greater resistance to targeted therapy and chemotherapy and better reflect patient response to therapy. Furthermore, HS-PDX can be grown in mice with humanized bone marrow to create humanized immune stroma patient-derived xenograft (HIS-PDX) models. The HIS-PDX 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 recruitment of TAMs and tumor immune exclusion to impact to response to immunologic therapy. We show an immunosuppressive role for human tumor stroma and that this model can be used to identify immunotherapeutic combinations to overcome stroma-mediated immunosuppression. Combined, our data confirm a critical role for human stroma in therapeutic response and indicate that HIS-PDX can be an important tool for preclinical drug testing.

The online version contains supplementary material available at 10.1007/s00262-026-04349-4.

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