ResearchIn-Press PreviewImmunology Open Access | 10.1172/jci.insight.156623
1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, indianapolis, United States of America
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States of America
3Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America
4IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America
5Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, United States of America
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1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, indianapolis, United States of America
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States of America
3Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America
4IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America
5Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, United States of America
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1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, indianapolis, United States of America
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States of America
3Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America
4IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America
5Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, United States of America
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1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, indianapolis, United States of America
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States of America
3Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America
4IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America
5Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, United States of America
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1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, indianapolis, United States of America
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States of America
3Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America
4IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America
5Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, United States of America
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1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, indianapolis, United States of America
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States of America
3Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America
4IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America
5Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, United States of America
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1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, indianapolis, United States of America
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States of America
3Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America
4IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America
5Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, United States of America
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1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, indianapolis, United States of America
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States of America
3Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America
4IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America
5Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, United States of America
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1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, indianapolis, United States of America
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States of America
3Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America
4IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America
5Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, United States of America
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1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, indianapolis, United States of America
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States of America
3Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States of America
4IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America
5Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, United States of America
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Published August 2, 2022 - More info
Lysosomal acid lipase (LAL) is a key enzyme in the metabolic pathway of neutral lipids. In the blood of LAL deficient (lal-/-) mice, increased CD11c+ cells were accompanied by up-regulated PD-L1 expression. Single cell RNA sequencing of lal-/- CD11c+ cells identified two distinctive clusters with a major metabolic shift towards glucose utilization and reactive oxygen species (ROS) over-production. Pharmacologically blocking pyruvate dehydrogenase in glycolysis not only reduced CD11c+ cells and their PD-L1 expression, but also reversed their capabilities of T cell suppression and tumor growth stimulation. Colony-stimulating factor 1 receptor (CSF1R) plays an essential role in controlling lal-/- CD11c+ cell homeostasis and function and PD-L1 expression. Inhibition of LAL activity by pharmacological inhibitor increased CD11c, PD-L1 and CSF1R levels in both normal murine myeloid cells and human blood cells. Tumor-bearing mice and human non-small-cell lung cancer (NSCLC) patients also showed CD11c+ cell expansion with PD-L1 and CSF1R up-regulation and immunosuppression. There were positive correlations among CD11c, PD-L1 and CSF1R expression and negative correlations with LAL expression in lung cancer and melanoma patients using the TCGA database and patient samples. Therefore, CD11c+ cells switched their functions to immune suppression and tumor growth stimulation through CSF1R/PD-L1 upregulation and metabolic reprogramming.