| First Author | Ding X | Year | 2021 |
| Journal | Am J Pathol | Volume | 191 |
| Issue | 2 | Pages | 353-367 |
| PubMed ID | 33159889 | Mgi Jnum | J:304380 |
| Mgi Id | MGI:6510434 | Doi | 10.1016/j.ajpath.2020.10.007 |
| Citation | Ding X, et al. (2021) Lysosomal Acid Lipase Deficiency Controls T- and B-Regulatory Cell Homeostasis in the Lymph Nodes of Mice with Human Cancer Xenotransplants. Am J Pathol 191(2):353-367 |
| abstractText | Utilization of proper preclinical models accelerates development of immunotherapeutics and the study of the interplay between human malignant cells and immune cells. Lysosomal acid lipase (LAL) is a critical lipid hydrolase that generates free fatty acids and cholesterol. Ablation of LAL suppresses immune rejection and allows growth of human lung cancer cells in lal(-/-) mice. In the lal(-/-) lymph nodes, the percentages of both T- and B-regulatory cells (Tregs and Bregs, respectively) are increased, with elevated expression of programmed death-ligand 1 and IL-10, and decreased expression of interferon-gamma. Levels of enzymes in the glucose and glutamine metabolic pathways are elevated in Tregs and Bregs of the lal(-/-) lymph nodes. Pharmacologic inhibitor of pyruvate dehydrogenase, which controls the transition from glycolysis to the citric acid cycle, effectively reduces Treg and Breg elevation in the lal(-/-) lymph nodes. Blocking the mammalian target of rapamycin or reactivating peroxisome proliferator-activated receptor gamma, an LAL downstream effector, reduces lal(-/-) Treg and Breg elevation and PD-L1 expression in lal(-/-) Tregs and Bregs, and improves human cancer cell rejection. Treatment with PD-L1 antibody also reduces Treg and Breg elevation in the lal(-/-) lymph nodes and improves human cancer cell rejection. These observations conclude that LAL-regulated lipid metabolism is essential to maintain antitumor immunity. |
