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Updated: Jun 16, 2026
Production and Characterization of Human Macrophages from Pluripotent Stem Cells
Published on: April 16, 2020
Anti PD-L1 immunotherapy alters macrophage phenotypes via EGR1 and HSP90AB1 supported by integrated methodologies
Xinyang Shou1, Yimin Wang1, Zhidong Zhou1
1The Third Affiliated Hospital of Zhejiang Chinese Medical University, No. 297 Moganshan Road, Hangzhou, 310006, Zhejiang, China.
Abstract:
Immune checkpoint inhibitors targeting programmed cell death ligand 1 (PD-L1) have transformed cancer therapy but have been linked to increased cardiovascular risk, particularly atherosclerosis (AS). This study hypothesized that anti-PD-L1 therapy promotes atherosclerosis progression by modulating macrophage phenotypes and enhancing foam cell formation via gene-level changes. Single-cell RNA sequencing (scRNA-seq) analysis of macrophages post-anti-PD-L1 immunotherapy was conducted using the GSE169246 dataset. Differential expression, GO/KEGG enrichment, and transcription factor analyses were performed. Cellular communication patterns were examined, and in vitro validation included foam cell assays and protein-level assessments. Anti-PD-L1 treatment promoted a shift toward pro-inflammatory M1 macrophages, increased foam cell formation, and upregulated EGR1 and HSP90AB1. These gene changes correlated with altered cellular interaction patterns, particularly between macrophages and endothelial cells. PD-L1 inhibition reprograms macrophage behavior through EGR1 and HSP90AB1-mediated pathways, driving M1 polarization and foam cell development. These findings reveal a mechanistic link between immunotherapy and AS progression and underscore the need for cardiovascular monitoring in patients undergoing PD-L1 blockade.
Insights
Immune checkpoint inhibitors targeting programmed cell death ligand 1 (PD-L1) increase cardiovascular risk by promoting atherosclerosis. Anti-PD-L1 therapy alters macrophage behavior, driving M1 polarization and foam cell formation, thus accelerating disease progression.
Area of Science:
- Immunology
- Cardiovascular Science
- Oncology
Background:
- Immune checkpoint inhibitors (ICIs) targeting programmed cell death ligand 1 (PD-L1) have revolutionized cancer therapy.
- However, ICIs are associated with increased cardiovascular risk, particularly atherosclerosis (AS).
Purpose of the Study:
- To investigate the mechanistic link between anti-PD-L1 therapy and atherosclerosis progression.
- To determine if anti-PD-L1 therapy modulates macrophage phenotypes and enhances foam cell formation through gene-level changes.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) analysis of macrophages from the GSE169246 dataset post-anti-PD-L1 immunotherapy.
- Differential gene expression, Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and transcription factor analyses.
- In vitro foam cell assays and protein-level assessments to validate findings.
Main Results:
- Anti-PD-L1 treatment induced a shift in macrophage phenotype towards pro-inflammatory M1 macrophages.
- Increased foam cell formation was observed in macrophages treated with anti-PD-L1.
- Upregulation of EGR1 and HSP90AB1 genes was identified, correlating with altered macrophage-endothelial cell interactions.
Conclusions:
- PD-L1 inhibition reprograms macrophage behavior via EGR1 and HSP90AB1 pathways, promoting M1 polarization and foam cell development.
- These findings establish a mechanistic link between immunotherapy and atherosclerosis progression.
- Cardiovascular monitoring is crucial for patients receiving PD-L1 blockade therapy.
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