Impaired lipid biosynthesis hinders anti-tumor efficacy of intratumoral iNKT cells.

ABSTRACT: Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPAR? and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-? production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPAR? in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-? production. Importantly, PPAR? agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-? production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis.

SUBMITTER: Fu S 

PROVIDER: S-EPMC6978340 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature