Resident Macrophage-Orchestrated Immune and Fibroblast Interactions in Immune Checkpoint Inhibitor-Associated...

Area of Science:

• Nephrology
• Immunology
• Oncology

Background:

• Immune checkpoint inhibitors (ICIs) revolutionize cancer treatment but can cause immune-related adverse events, including ICI-associated nephrotoxicity (ICI-AN).
• The underlying mechanisms of ICI-AN are not fully understood, hindering diagnostic and therapeutic advancements.
• Understanding ICI-AN pathogenesis is crucial for managing cancer therapy side effects.

Purpose of the Study:

• To elucidate the cellular and molecular mechanisms driving ICI-associated nephrotoxicity.
• To identify potential diagnostic biomarkers and therapeutic targets for ICI-AN.
• To investigate the role of resident macrophages in ICI-AN.

Main Methods:

• Integrated analysis of imaging mass cytometry, transcriptomics, and murine models.
• Examination of kidney biopsies from ICI-AN patients.
• Utilized anti-PD-1 treatment in mice to model renal injury.

Main Results:

• ICI-AN patient biopsies showed increased resident macrophages, fibroblasts, and CD8+ T cells, with macrophages expressing pro-inflammatory and pro-fibrotic markers.
• Anti-PD-1 therapy in mice induced renal injury, characterized by immune cell infiltration, tubular damage, and fibrosis.
• Depleting resident macrophages reduced renal injury and fibrosis by decreasing CXCL9 and MMP12 expression, without affecting anti-tumor efficacy.

Conclusions:

• Resident macrophages are key drivers of ICI-associated nephrotoxicity.
• Urinary CXCL9 levels may serve as a diagnostic biomarker for ICI-AN.
• MMP12, expressed by resident macrophages, is a potential therapeutic target for mitigating ICI-AN.
• This research offers novel insights into ICI-AN pathogenesis and strategies for managing nephrotoxicity.