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Nephrotoxicity of Immune Checkpoint Inhibitors in Mice with a Human Immune System
Sarah Asby1, Xia Wen2, Michael Goedken2,3
1Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO.
Introduction:
Immune checkpoint inhibitors (ICIs) enhance antitumor responses by blocking inhibitory receptors, including PD-1 and CTLA-4. Overactivation can trigger systemic toxicity akin to autoimmune diseases, including kidney manifestations. We sought to 1) profile immune signaling and 2) interrogate potential mechanisms of ICI-related kidney injury in a Human Immune System (HIS) tumor-bearing mouse model treated with nivolumab and ipilimumab.
Methods:
Immunodeficient BRGS (BALB/c-Rag2 null Il2rγ null Sirpα NOD) neonates were engrafted with human CD34+ cells to generate HIS-BRGS mice. Human MDA-MB-231 tumor cells were implanted subcutaneously; once tumors reached ~150 mm3, mice received weekly intraperitoneal vehicle (PBS) or ICI (nivolumab 20 mg/kg + ipilimumab 10 mg/kg) for 4 weeks (Veh BRGS n=4; ICI BRGS n=6; Veh HIS-BRGS n=7; ICI HIS-BRGS n=7). Kidneys were evaluated by histopathology (H&E, TEM), flow cytometry for human immune phenotypes, multiplex ELISA (80 human proteins; 10 injury biomarkers), bulk RNA sequencing, and targeted qPCR. Pearson correlations identified predictors of histopathological injury.
Results:
Renal vasculitis and interstitial nephritis were observed only in ICI-treated HIS-BRGS mice. These kidneys showed a shift toward CD4+ T-cell enrichment with an increased TNF-α production capacity compared to CD8+ counterparts. Toxicity was accompanied by increased renal concentrations of human cytokines, chemokines, and soluble receptors. ICI treatment significantly elevated serine proteases (Granzyme A/B) and NGF-β, while decreasing IL-4. Interstitial nephritis correlated with renal PD-1 and MIF. Renal vasculitis correlated with kidney PD-1, CCL1, MIF, Granzyme A, IL-15, and BAFF. Traditional injury biomarkers (KIM-1, NGAL) remained unchanged; however, a trending decrease in EGF was observed.
Conclusions:
Our study suggests that shifts in human T-cell populations and specific immune proteins could serve as promising biomarkers and mechanistic targets for ICI nephrotoxicity. The tumor-bearing HIS-BRGS mouse model reproducibly recapitulates the histopathological and immunological features of human ICI-induced nephrotoxicity and represents a validated preclinical platform for testing novel therapeutic interventions to preserve kidney function during cancer immunotherapy.
Insights
Immune checkpoint inhibitors (ICIs) can cause kidney injury. This study used a humanized mouse model to identify immune signaling pathways and biomarkers associated with ICI-related nephrotoxicity, offering a platform for new therapies.
Area of Science:
- Immunology
- Nephrology
- Oncology
Background:
- Immune checkpoint inhibitors (ICIs) like PD-1 and CTLA-4 block inhibitory receptors to enhance antitumor responses.
- Overactivation of ICIs can lead to systemic toxicity, resembling autoimmune diseases, including kidney damage (nephrotoxicity).
- Understanding the mechanisms of ICI-induced kidney injury is crucial due to its clinical relevance (up to 25% of patients) and the lack of human biopsy data.
Purpose of the Study:
- To profile immune signaling in a humanized mouse model treated with ICIs.
- To investigate potential mechanisms underlying ICI-related kidney injury.
- To establish a preclinical model for studying ICI nephrotoxicity.
Main Methods:
- Humanized Immune System (HIS) BRGS mice bearing human tumors were treated with vehicle or combined nivolumab and ipilimumab.
- Kidneys were analyzed using histopathology, flow cytometry, multiplex ELISA, RNA sequencing, and qPCR.
- Correlations between immune markers and histopathological injury were assessed.
Main Results:
- ICI-treated HIS-BRGS mice developed renal vasculitis and interstitial nephritis.
- A CD4+ T-cell dominant infiltrate with increased TNF-α production was observed in affected kidneys.
- Specific immune proteins (e.g., IL-15, CCL1, MIF, Granzyme A, BAFF) correlated with renal pathology severity.
Conclusions:
- Shifts in human T-cell populations and specific immune proteins are potential biomarkers and mechanistic targets for ICI nephrotoxicity.
- The HIS-BRGS mouse model effectively recapitulates human ICI-induced kidney injury.
- This model serves as a validated platform for testing interventions to mitigate ICI nephrotoxicity.
