Lysosomal Acid Lipase Deficiency Controls Treg and Breg Homeostasis in the Lymph Nodes of Mice with Human Cancer Xenotransplants.

Utilization of proper preclinical models accelerates development of immunotherapeutic 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 regulatory and B regulatory cells (Tregs and Bregs) are increased with elevated expression of PD-L1, IL-10, and decreased expression of IFNγ. In Tregs and Bregs of the lal-/- lymph nodes, levels of enzymes in glucose and glutamine metabolic pathways are elevated. Pharmacologic inhibitor of pyruvate dehydrogenase (PDH), 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 (mTOR) or reactivating peroxisome proliferator-activated receptor gamma (PPARγ), an LAL downstream effector, reduces lal-/- Treg and Breg elevation, PD-L1 expression in lal-/- Tregs and Bregs, and improves human cancer cell rejection. Treatment of 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 anti-tumor immunity.