Ding_2021_Am.J.Pathol_191_353

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.