TNF-α blockade mitigates immune checkpoint-related nephritis in a humanized mouse model

Area of Science:

• Immunology
• Nephrology
• Pharmacology

Background:

• Immune checkpoint inhibitors (ICIs) are crucial cancer therapies but can induce immune-related adverse events (irAEs).
• Acute interstitial nephritis (AIN) is a common irAE, potentially linked to interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) pathway activation.
• The precise mechanisms underlying ICI-induced AIN and effective preventative strategies require further elucidation.

Purpose of the Study:

• To investigate the renal effects of ICIs in a humanized mouse model.
• To explore the synergistic role of ICIs and pro-inflammatory cytokines in AIN development.
• To evaluate the efficacy of selective TNF-α blockade in preventing ICI-AIN.

Main Methods:

• Utilized a humanized chimeric PD-1/PD-L1 mouse model for ICI administration.
• Assessed renal function, plasma cytokine profiles, and kidney histology (microscopy, single-cell RNA sequencing).
• Compared four groups: Control, ICI-Only, ICI-Cytokines, and ICI-TNF-α blockade.

Main Results:

• ICI treatment led to increased renal infiltration of CD4+/CD8+ T cells.
• TNF-α blockade significantly decreased renal TNF-α and plasma IFN-γ levels.
• ICI-Block mice exhibited lower plasma IL-6, MCP-1, and TNF-α, with reduced renal inflammation.

Conclusions:

• The humanized model effectively replicates key features of ICI-AIN.
• A synergistic interaction between ICIs and pro-inflammatory cytokines contributes to ICI-AIN.
• Selective TNF-α blockade shows promise in mitigating the risk of ICI-AIN, warranting further clinical investigation.