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

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

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.

Authors

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

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Figure 2

Lal–/– CD11c+ cells suppress T cell proliferation and stimulate tumor cell growth through PD-L1.

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Lal–/– CD11c+ cells suppress T cell proliferation and stimulate tumor c...
(A) CFSE-labeled Lal+/+ CD4+ T cells were stimulated with anti-CD3 mAb plus anti-CD28 mAb for 4 days in the presence or absence of Lal+/+ or Lal–/– CD11c+ cells at a 1:1 CD4+ T cell/CD11c+ cell ratio. Proliferation of labeled CD4+ T cells was analyzed by flow cytometry. Peaks represent cell division cycles. PBS was used as a negative control. Left: A representative CFSE dilution by flow cytometry. Right: Statistical analyses of percentage of divided CD4+ T cells. (B) Ratios of CD4+ T cells to CD11c+ cells and CD8+ T cells to CD11c+ cells in the blood of Lal–/– versus Lal+/+ mice were analyzed by flow cytometry analysis. (C) Freshly isolated Lal+/+ or Lal–/– CD11c+ cells were pretreated with IgG or anti–PD-L1 antibody (5 μg/mL), then cocultured with CFSE-labeled Lal+/+ CD4+ T cells (at 1:1 ratio) for T cell proliferation assay as described for A. (D) B16 melanoma cells (2 × 105) were mixed with Lal+/+ or Lal–/– CD11c+ cells (2 × 105) and injected subcutaneously at the flank region of Lal+/+ recipient mice. Tumor size was measured at 7, 10, 14, 17, and 21 days after cell injection and determined using the formula (length × width2)/2. (E) Lal+/+ or Lal–/– CD11c+ cells were pretreated with IgG or anti–PD-L1 antibody (5 μg/mL), then coinjected with B16 melanoma cells into the flank region of Lal+/+ recipient mice. Data are expressed as mean ± SD. Experiments were independently repeated, n = 5 for A–C, n = 10 for D, n = 16 for E. **P < 0.01, 1-way ANOVA for A and E, unpaired Student’s t test for B and D, 2-way ANOVA for C.