Abstract
Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs), with acute interstitial nephritis (ICI-AIN) being the most common irAE. While the exact mechanism remains unclear, upregulation of IFN-γ and TNF-α pathways has been implicated. This study used a humanized chimeric PD-1/PD-L1 mouse model to assess renal effects of ICIs, alone or combined with proinflammatory cytokines, and to test if selective TNF-α blockade could prevent ICI-AIN. Mice were randomly divided into 4 experimental groups: Control, ICI-Only, ICI-Cytokines (ICI-Cyt), and ICI-Block (ICI-TNF-α blockade). Renal function and cytokine profiles were assessed, while kidney tissue was analyzed using microscopy and single-cell RNA-seq. Histology revealed increased renal infiltration of CD4+/CD8+ T cells in ICI-treated groups and decreased TNF-α expression following TNF-α blockade. Additionally, kidney tissue ELISA demonstrated reduced IFN-γ levels following TNF-α blockade. Plasma IL-6, MCP-1, and TNF-α were lower in ICI-Block mice. Single-cell RNA-seq revealed shifts in immune cell populations and genes of interest including Bcl2a1, Icos, Il18r1, Ccr2, and Jaml. This humanized model replicates ICI-AIN key features, revealing a synergistic role of ICIs and proinflammatory cytokines. TNF-α blockade demonstrated protective effects, supporting its potential role in mitigating the risk of ICI-AIN.
Authors
Victor D. Cuenca Narvaez, Coraima Nava Chavez, Omar Al Refai, Johanna E.J. Jacobs, Luis E. Gutierrez, Song Zhang, Xiaoyan Li, Jacob B. Hirdler, Michael F. Romero, Joerg Herrmann, Xiaogang Li, Haidong Dong, Alfonso Eirin, Sandra M. Herrmann
Figure 5
Biological analysis of gene expression for upregulated genes.
