Cisplatin presentation to CD4 T cells involves robust activation and immunotoxicity 2258176

Abstract

Abstract Introduction Cisplatin, a platinum-based chemotherapeutic agent, remains one of the most efficacious drugs in the clinical management of a broad spectrum of malignancies. Despite its therapy, Cisplatin causes off-target toxicity like hepatotoxicity, neurotoxicity, and especially nephrotoxicity leading to chronic renal impairment. The role of Cisplatin in immunotoxicity is largely unknown, except for its formation of DNA adducts, leading to replication stress and trigger apoptosis in neoplastic cells. The objective of this study is to test whether CD4+ T cells react to platinum (Pt)-containing compounds, and to characterize their role in T cell activation and potential contribution to Pt-induced kidney tissue pathology. To this end, we evaluated the immunogenicity of several Pt-based agents, including Carboplatin (CarbPt), Oxaliplatin (OxaliPt), a Pt-Standard compound, and a Multi-Element Platinum (ME-Pt) formulation. Methods We performed the IL2 assay to evaluate CZD9.2 T cell activation. Morphological changes and cell death were observed through microscopy imaging. Immune cell infiltration was assessed using IHC staining. Results Compared to Nickel, CisPt, CarbPt, OxaliPt, and Pt-standard, Pt ion can be presented by DR1-expressing APCs, and induces strong CZD9.2 TCR activation. CisPt showed low T cell cytotoxicity and can stimulate T cells at high concentrations. The ME-Pt is highly toxic and does not activate CZD9.2 TCR. Antibody blockade assays revealed that the unbound forms of Cisplatin and related Pt compounds can activate CD4+ T cells by modifying the HLA/peptide complex, independent of classical antigen processing pathways. Conclusion For the first time, we identified a Pt-responsive CD4 T cell clone. Cisplatin can robustly stimulate human CD4+ T cell responses through the release of Pt ions. These findings suggested that the Pt ion could potently modify the surface of MHCII/peptide and directly bind the CZD9.2 TCR, potentially contributing to localized inflammation and organ-specific toxicity. Funding Source NIDDK Topic Categories Classical and Non-Classical Antigen Presenting Cells (APC)