Critical role of PPARγ in myeloid-derived suppressor cell-stimulated cancer cell proliferation and metastasis

Lysosomal acid lipase (LAL) is a key enzyme controlling neutral lipid metabolic signaling in myeloid-derived suppressor cells (MDSCs). MDSCs from LAL-deficient (lal(-/-)) mice directly stimulate cancer cell proliferation. PPAR gamma ligand treatment inhibited lal(-/-) MDSCs stimulation of tumor cell growth and metastasis in vivo, and tumor cell proliferation and migration in vitro. In addition, PPAR gamma ligand treatment impaired lal(-/-) MDSCs transendothelial migration, and differentiation from lineage-negative cells. The corrective effects of PPAR gamma ligand on lal(-/-) MDSCs functions were mediated by regulating the mammalian target of rapamycin (mTOR) pathway, and subsequently blocking MDSCs ROS overproduction. Furthermore, in the myeloid-specific dominant-negative PPAR gamma (dnPPAR gamma) overexpression bitransgenic mouse model, tumor growth and metastasis were enhanced, and MDSCs from these mice stimulated tumor cell proliferation and migration. MDSCs with dnPPAR gamma overexpression showed increased transendothelial migration, overactivation of the mTOR pathway, and ROS overproduction. These results indicate that PPAR gamma plays a critical role in neutral lipid metabolic signaling controlled by LAL, which provides a mechanistic basis for clinically targeting MDSCs to reduce the risk of cancer proliferation, growth and metastasis.