Lysosomal acid lipase, CSF1R and PD-L1 determine functions of CD11c+ myeloid-derived suppressor cells

Ting Zhao; Sheng Liu; Xinchun Ding; Erica M. Johnson; Nasser H. Hanna; Kanhaiya Singh; Chandan K. Sen; Jun Wan; Hong Du; Cong Yan

doi:10.1172/jci.insight.156623

Lysosomal acid lipase, CSF1R and PD-L1 determine functions of CD11c+ myeloid-derived suppressor cells

Ting Zhao,¹ Sheng Liu,² Xinchun Ding,¹ Erica M. Johnson,¹ Nasser H. Hanna,⁴ Kanhaiya Singh,⁵ Chandan K. Sen,⁵ Jun Wan,² Hong Du,¹ and Cong Yan¹

Published August 2, 2022 - More info

View PDF

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 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.

Lysosomal acid lipase, CSF1R and PD-L1 determine functions of CD11c+ myeloid-derived suppressor cells

Ting Zhao,¹ Sheng Liu,² Xinchun Ding,¹ Erica M. Johnson,¹ Nasser H. Hanna,⁴ Kanhaiya Singh,⁵ Chandan K. Sen,⁵ Jun Wan,² Hong Du,¹ and Cong Yan¹

Article tools

Metrics

Go to

Lysosomal acid lipase, CSF1R and PD-L1 determine functions of CD11c+ myeloid-derived suppressor cells

Ting Zhao,1 Sheng Liu,2 Xinchun Ding,1 Erica M. Johnson,1 Nasser H. Hanna,4 Kanhaiya Singh,5 Chandan K. Sen,5 Jun Wan,2 Hong Du,1 and Cong Yan1

Article tools

Metrics

Go to

Sign up for email alerts

Ting Zhao,¹ Sheng Liu,² Xinchun Ding,¹ Erica M. Johnson,¹ Nasser H. Hanna,⁴ Kanhaiya Singh,⁵ Chandan K. Sen,⁵ Jun Wan,² Hong Du,¹ and Cong Yan¹