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Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c(+) myeloid-derived suppressor cells
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 upregulated programmed cell death ligand 1 (PD-L1) expression. Single-cell RNA sequencing of Lal(–/–) CD11c(+) cells ide...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society for Clinical Investigation
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9536279/ https://www.ncbi.nlm.nih.gov/pubmed/35917184 http://dx.doi.org/10.1172/jci.insight.156623 |
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author | Zhao, Ting Liu, Sheng Ding, Xinchun Johnson, Erica M. Hanna, Nasser H. Singh, Kanhaiya Sen, Chandan K. Wan, Jun Du, Hong Yan, Cong |
author_facet | Zhao, Ting Liu, Sheng Ding, Xinchun Johnson, Erica M. Hanna, Nasser H. Singh, Kanhaiya Sen, Chandan K. Wan, Jun Du, Hong Yan, Cong |
author_sort | Zhao, Ting |
collection | PubMed |
description | 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 upregulated programmed cell death ligand 1 (PD-L1) expression. Single-cell RNA sequencing of Lal(–/–) CD11c(+) cells identified 2 distinctive clusters with a major metabolic shift toward glucose utilization and reactive oxygen species overproduction. 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) played an essential role in controlling Lal(–/–) CD11c(+) cell homeostasis and function and PD-L1 expression. Pharmacological inhibition of LAL activity increased CD11c, PD-L1, and CSF1R levels in both normal murine myeloid cells and human blood cells. Tumor-bearing mice and human patients with non–small cell lung cancer also showed CD11c(+) cell expansion with PD-L1 and CSF1R upregulation and immunosuppression. There were positive correlations among CD11c, PD-L1, and CSF1R expression and negative correlations with LAL expression in patients with lung cancer or melanoma using The Cancer Genome Atlas 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. |
format | Online Article Text |
id | pubmed-9536279 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-95362792022-10-07 Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c(+) myeloid-derived suppressor cells Zhao, Ting Liu, Sheng Ding, Xinchun Johnson, Erica M. Hanna, Nasser H. Singh, Kanhaiya Sen, Chandan K. Wan, Jun Du, Hong Yan, Cong JCI Insight Research Article 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 upregulated programmed cell death ligand 1 (PD-L1) expression. Single-cell RNA sequencing of Lal(–/–) CD11c(+) cells identified 2 distinctive clusters with a major metabolic shift toward glucose utilization and reactive oxygen species overproduction. 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) played an essential role in controlling Lal(–/–) CD11c(+) cell homeostasis and function and PD-L1 expression. Pharmacological inhibition of LAL activity increased CD11c, PD-L1, and CSF1R levels in both normal murine myeloid cells and human blood cells. Tumor-bearing mice and human patients with non–small cell lung cancer also showed CD11c(+) cell expansion with PD-L1 and CSF1R upregulation and immunosuppression. There were positive correlations among CD11c, PD-L1, and CSF1R expression and negative correlations with LAL expression in patients with lung cancer or melanoma using The Cancer Genome Atlas 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. American Society for Clinical Investigation 2022-09-08 /pmc/articles/PMC9536279/ /pubmed/35917184 http://dx.doi.org/10.1172/jci.insight.156623 Text en © 2022 Zhao et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Zhao, Ting Liu, Sheng Ding, Xinchun Johnson, Erica M. Hanna, Nasser H. Singh, Kanhaiya Sen, Chandan K. Wan, Jun Du, Hong Yan, Cong Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c(+) myeloid-derived suppressor cells |
title | Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c(+) myeloid-derived suppressor cells |
title_full | Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c(+) myeloid-derived suppressor cells |
title_fullStr | Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c(+) myeloid-derived suppressor cells |
title_full_unstemmed | Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c(+) myeloid-derived suppressor cells |
title_short | Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c(+) myeloid-derived suppressor cells |
title_sort | lysosomal acid lipase, csf1r, and pd-l1 determine functions of cd11c(+) myeloid-derived suppressor cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9536279/ https://www.ncbi.nlm.nih.gov/pubmed/35917184 http://dx.doi.org/10.1172/jci.insight.156623 |
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