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Updated: May 28, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Pathological findings of immunotherapy-induced nephrotoxicity in a humanized immune system mouse model
Sarah C Asby1, Lauren E Thompson1, Michael Goedken2
1Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado, USA.
Abstract:
While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, they can elicit organ-related immune-related adverse events (irAEs) such as kidney injury. Here, our study evaluated the ability of a humanized immune system (HIS) tumor-bearing mouse model to investigate ICI-mediated kidney injury. Non-humanized (BRGS) and humanized (HIS-BRGS) mice were implanted with human breast cancer cells and treated with either nivolumab (anti-PD-1) or a combination of nivolumab and ipilimumab (anti-CTLA-4) for four weeks. Histopathological analysis revealed that HIS-BRGS mice treated with ICIs exhibited significant interstitial nephritis and vasculitis/periarteritis, consistent with kidney phenotypes observed in patients. Combination therapy resulted in more extensive kidney pathology than nivolumab alone and exhibited an accumulation of T helper cells in the affected areas. Importantly, our results suggest that HIS-BRGS mice can effectively recapitulate features of ICI-induced kidney injury observed in patients and can be used to study mechanisms and prevention strategies to limit irAEs.
Insights
A humanized immune system mouse model effectively mimics immune checkpoint inhibitor-induced kidney injury, showing significant pathology similar to patients. This model aids in studying prevention strategies for these cancer therapy side effects.
Area of Science:
- Immunology
- Oncology
- Nephrology
Background:
- Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but can cause immune-related adverse events (irAEs), including kidney injury.
- Understanding the mechanisms of ICI-induced kidney injury is crucial for patient safety and effective treatment.
Purpose of the Study:
- To evaluate a humanized immune system (HIS) tumor-bearing mouse model for studying ICI-mediated kidney injury.
- To assess the histopathological changes in kidney tissue following ICI treatment in HIS mice.
Main Methods:
- Humanized (HIS-BRGS) and non-humanized (BRGS) mice were implanted with human breast cancer cells.
- Mice received nivolumab (anti-PD-1) or a combination of nivolumab and ipilimumab (anti-CTLA-4) for four weeks.
- Histopathological analysis was performed on kidney tissues to evaluate injury.
Main Results:
- HIS-BRGS mice treated with ICIs developed interstitial nephritis and vasculitis/periarteritis, mirroring human kidney irAEs.
- Combination therapy (nivolumab + ipilimumab) induced more severe kidney pathology than nivolumab alone.
- T helper cell accumulation was observed in ICI-treated HIS-BRGS mouse kidneys.
Conclusions:
- The HIS-BRGS mouse model accurately recapitulates key features of ICI-induced kidney injury seen in patients.
- This model serves as a valuable tool for investigating the mechanisms underlying ICI-related kidney injury.
- The model can be utilized to develop and test strategies for preventing or mitigating kidney irAEs.
