Abstract: TH-PO1144
Cisplatin Immunotoxicity in Nickel-Responsive CD4 T Cells, Mouse Kidney, and Urine of Patients with Cancer
Session Information
- Onconephrology: Emerging Biomarkers, Preclinical Models, Clinical Challenges, and Therapeutic Strategies
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Onconephrology
- 1600 Onconephrology
Authors
- Tomar, Munendra Singh, University of Colorado Anschutz Medical Campus Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, United States
- Zhuang, Yonghua L., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Asby, Sarah C., University of Colorado Anschutz Medical Campus Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, United States
- Jaimes, Edgar A., Memorial Sloan Kettering Cancer Center, New York, New York, United States
- O'Bryant, Cindy L., University of Colorado Anschutz Medical Campus Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, United States
- Aleksunes, Lauren, Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States
- Joy, Melanie S., University of Colorado Anschutz Medical Campus Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, United States
Background
Cisplatin (CisPt) causes direct cytotoxicity to kidney tubules; however, ability to elicit immune responses in kidneys is unknown. As Pt is a transition metal similar to immunotoxic metals like Nickel, we speculated that CisPt could alter T cell responses. The purpose of the study was to 1) investigate whether Pt compounds elicit CD4+ T cell responses through cross-reactivity with Nickel-reactive T cells, 2) quantify CD4 T cells in the kidneys of CisPt-treated mice, and 3) profile proteomic signatures of T cell activation and migration pathways in the urines of CisPt-treated cancer patients.
Methods
The Nickel-reactive CD4+ Treg cell clone (CZD9.2) was co-cultured with DAP3.DR1 cells (APCs) and exposed to Pt compounds (CisPt, oxaliplatin, carboplatin, Pt-std, and ME-Pt) for 24 h. Supernatant was collected to measure T cell activation by IL-2 secretion (HT2 assay). Mouse kidneys - C57BL/6 mice (Charles River, MA), 4 days post single CisPt 20 mg/kg i.p. dose were evaluated by IHC staining for CD4+ T cells. Urine from CisPt treated cancer patients (n=20; NCT03817970) at baseline and 48 h after first/second dose were quantified with SomaLogic v4.1 7k. Functional enrichment analysis of DE proteins was performed using Gene Set Enrichment Analysis (GSEA). All other results were analyzed using one-way ANOVA, two-tailed unpaired t-test, or Tukey’s multiple comparison tests (GraphPad Prism).
Results
Compared with nickel (positive control), CisPt, CarbPt, OxaliPt, and Pt-std can be presented by DR1-expressing APCs and elicit activation of the CZD9.2 TCR. A definitive dose-response relationship was observed between CisPt and Il-2 secretion, with CisPt 100 μM producing an equivalent response to nickel 150 μM. Activation of Pt-reactive T cells occurs independently of antigen uptake and intracellular processing (fixed APC assays). IHC staining after cisplatin treatment revealed CD4+ T cells in mouse kidneys. T-cell relevant pathways identified in urine of human subjects (age 60±12y, sex 16M:4 F, CisPt dose 121±56 mg) were migration, activation, proliferation, regulation, differentiation, cytotoxicity, and tolerance induction.
Conclusion
Pt-based drugs can effectively stimulate human CD4+ T cell responses by releasing Pt ions, revealing a novel and intriguing immunomodulatory mechanism. The study results across three separate models suggest CisPt may directly induce kidney injury through immunotoxicity.
Funding
- Other NIH Support