Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c+ myeloid-derived suppressor cells
dc.contributor.author | Zhao, Ting | |
dc.contributor.author | Liu, Sheng | |
dc.contributor.author | Ding, Xinchun | |
dc.contributor.author | Johnson, Erica M. | |
dc.contributor.author | Hanna, Nasser H. | |
dc.contributor.author | Singh, Kanhaiya | |
dc.contributor.author | Sen, Chandan K. | |
dc.contributor.author | Wan, Jun | |
dc.contributor.author | Du, Hong | |
dc.contributor.author | Yan, Cong | |
dc.contributor.department | Pathology and Laboratory Medicine, School of Medicine | |
dc.date.accessioned | 2023-09-05T15:26:51Z | |
dc.date.available | 2023-09-05T15:26:51Z | |
dc.date.issued | 2022-09-08 | |
dc.description.abstract | 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. | |
dc.eprint.version | Final published version | |
dc.identifier.citation | Zhao T, Liu S, Ding X, et al. Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c+ myeloid-derived suppressor cells. JCI Insight. 2022;7(17):e156623. Published 2022 Sep 8. doi:10.1172/jci.insight.156623 | |
dc.identifier.uri | https://hdl.handle.net/1805/35377 | |
dc.language.iso | en_US | |
dc.publisher | The American Society for Clinical Investigation | |
dc.relation.isversionof | 10.1172/jci.insight.156623 | |
dc.relation.journal | JCI Insight | |
dc.rights | Attribution 4.0 International | en |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.source | PMC | |
dc.subject | Immunology | |
dc.subject | Cancer immunotherapy | |
dc.subject | Lung neoplasms | |
dc.title | Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c+ myeloid-derived suppressor cells | |
dc.type | Article |