Abstract: FR-PO197
Histologic and Immunologic Phenotypes of Immune Checkpoint Inhibitor-Mediated Nephrotoxicity in a Novel Humanized Immune System Mouse Model
Session Information
- Onconephrology: Immunotherapy Nephrotoxicity and Assessment of GFR
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Onconephrology
- 1700 Onconephrology
Authors
- Asby, Sarah C., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Thompson, Lauren E., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Goedken, Michael J., Rutgers The State University of New Jersey, Piscataway, New Jersey, United States
- Lanis, Jordi, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Kostka-Newman, Zander C., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Pelanda, Roberta, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Lang, Julie, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Aleksunes, Lauren, Rutgers The State University of New Jersey, Piscataway, New Jersey, United States
- Joy, Melanie S., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
Background
Kidney immune-related adverse events (irAEs) following cancer treatment with immune checkpoint inhibitors (ICIs) have been observed in 5-25% of patients, with approximately 20% developing new onset chronic kidney disease within 5 years. Humanized immune systems (HIS) mouse models, as opposed to conventional syngeneic pre-clinical mouse models, represent a promising avenue for detecting and evaluating irAEs. The purpose of this study was to characterize the histologic and immunologic phenotypes of ICI-mediated kidney toxicity in humanized immune system (HIS) mice.
Methods
At 17-21 weeks of age, non-humanized (BRGS) and humanized (HIS-BRGS) mice were implanted s.c. with MDA-MB-231 cancer cells and treated with vehicle (PBS) or a combination of ipilimumab and nivolumab (ipi/nivo 10 mg/kg each 1x/wk) i.p. for 4 weeks. H&E-stained sections of kidneys were analyzed for histomorphological evidence of injury with incidence and severity scores (0=none, 1=mild, 2=moderate, and 3=severe), rank ordered and assessed by two-way ANOVA. Tissue sections from formalin-fixed kidneys were co-stained for molecular markers of human immune cell populations and single cell spatial proteomics performed using ChipCytometry (Canopy Biosciences). Flow cytometry was performed on collected tissues and assessed using Welch and Brown-Forsythe ANOVA. P<0.05 was considered statistically significant.
Results
Ipi/nivo treatment significantly reduced tumor weight compared to vehicle in HIS-BRGS mice (p<0.01). Histological evaluation from ipi/nivo treated HIS-BRGS mice showed increased incidence and severity of renal pathologies including vasculitis/periarteritis (p<0.001) and interstitial nephritis (p<0.05) compared to vehicle-treated HIS-BRGS mice and non-humanized BRGS mice (p<0.001). Ipi/nivo-treated HIS-BRGS mice showed reductions in the % CD8+ T cells and CD4+ T reg cells (p<0.05, p<0.06) and increase in % TNFα+ CD4+ T cells in the kidneys (p<0.05). Single cell proteomics showed a majority of CD4+ T helper vs. CD8+ cytotoxic T cells of total CD45+ cells in the region of kidney injury.
Conclusion
This study demonstrated the utility of a novel HIS mouse model as a translational tool to study the histological and immunological phenotype of ICI-mediated kidney injury.
Funding
- Other NIH Support