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A novel humanized immune stroma PDX cancer model for therapeutic studies
Dongli Yang1,2, Ian Beddows3, Huijuan Tang1
1Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, UPMC Hillman Cancer Center and the Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA.
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.
Insights
New human stroma-patient-derived xenograft (HS-PDX) models incorporate human tumor stroma, improving preclinical testing. These models better predict patient response to therapies, including immunotherapies, by reflecting stroma
Area of Science:
- Oncology
- Preclinical Cancer Models
- Drug Discovery
Background:
- Standard preclinical human tumor models lack human tumor stroma, a key component influencing therapeutic resistance.
- This deficiency may limit the stringency and predictive power of current models for novel cancer therapies.
Purpose of the Study:
- To develop an advanced preclinical tumor model that incorporates human tumor stroma for more accurate drug testing.
- To evaluate the utility of this new model in predicting patient response to targeted therapy, chemotherapy, and immunotherapy.
Main Methods:
- Creation of human stroma-patient-derived xenograft (HS-PDX) models using patient-derived tumor cells, cancer-associated mesenchymal stem/progenitor cells, and human endothelial cells.
- Development of humanized immune stroma-patient-derived xenograft (HIS-PDX) models by engrafting HS-PDX in mice with humanized bone marrow.
- Comparative analysis of HS-PDX and standard PDX models regarding therapeutic resistance and patient response correlation.
- RNA sequencing to assess genomic correlation between HIS-PDX models and primary human tumors.
- Investigation of the impact of human tumor stroma on immune cell infiltration (e.g., TAMs) and response to immunotherapies.
Main Results:
- HS-PDX models exhibited greater resistance to targeted therapy and chemotherapy compared to standard PDX models.
- HS-PDX models demonstrated a higher correlation with patient responses to therapy.
- HIS-PDX models successfully incorporated human connective tissues, vascular components, and immune cell infiltrates, showing 94-96% RNA sequencing correlation with primary human tumors.
- Human tumor stroma was shown to influence the recruitment of tumor-associated macrophages (TAMs) and promote tumor immune exclusion, impacting immunotherapy response.
- A significant immunosuppressive role of human tumor stroma was identified, highlighting its potential to be targeted by immunotherapeutic combinations.
Conclusions:
- The developed HS-PDX and HIS-PDX models accurately recapitulate the human tumor microenvironment, including stroma and immune components.
- These advanced models are crucial for preclinical drug testing, offering improved prediction of therapeutic efficacy and patient outcomes.
- The HIS-PDX model serves as a valuable tool for identifying novel immunotherapeutic strategies to overcome stroma-mediated immunosuppression in cancer.
