Immune checkpoint blockade targets macrophage PD-1 to exacerbate metabolic dysfunction

Area of Science:

• Immunology
• Metabolic Science
• Molecular Biology

Background:

• Immune checkpoint inhibitor (ICI) therapies, particularly anti-PD-1 treatments, are associated with the induction of metabolic dysfunction.
• The precise molecular mechanisms linking ICI therapy to systemic metabolic disorders remain incompletely understood.

Purpose of the Study:

• To identify the key molecular mediators responsible for anti-PD-1 treatment-induced exacerbation of systemic metabolic disorders.
• To elucidate the role of macrophage programmed cell death protein 1 (PD-1) in mediating metabolic dysfunction during ICI therapy.

Main Methods:

• Investigated the role of macrophage PD-1 in the context of anti-PD-1 therapy using relevant preclinical models.
• Analyzed the impact of macrophage PD-1 blockade on endoplasmic reticulum stress, inflammatory responses, adipose tissue thermogenesis, and overall energy expenditure.

Main Results:

• Macrophage programmed cell death protein 1 (PD-1) was identified as a critical molecular mediator of anti-PD-1 treatment-induced metabolic dysfunction.
• Blockade of macrophage PD-1 was shown to disrupt its non-canonical function in suppressing endoplasmic reticulum stress-mediated inflammatory responses.
• Impaired adipose tissue thermogenesis and reduced energy expenditure were observed following macrophage PD-1 blockade, contributing to systemic metabolic disorders.

Conclusions:

• Macrophage PD-1 plays a crucial role in regulating metabolic homeostasis during immune checkpoint inhibitor therapy.
• Targeting macrophage PD-1 may offer a strategy to mitigate the metabolic side effects associated with anti-PD-1 treatments.
• Understanding the moonlighting functions of PD-1 in macrophages is essential for managing ICI-related metabolic complications.