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 PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ 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.
Highlights
Dysfunction of invariant natural killer T cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear
We show that activation of invariant natural killer T (iNKT) cells increases their lipid biosynthesis, and that is promoted by PPARγ in cooperation with PLZF and is required for the optimal IFN-γ production
PIO, the agonist of PPARγ, further enhanced the amount of these intracellular fatty acids in activated iNKT cells, whereas T007, the antagonist of PPARγ, significantly reduced the amount of these fatty acids (Fig. 1f). These results suggested that PPARγ activity controlled the amount of fatty acids in iNKT cells
Summary
Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. We report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf[1]. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces PPARγ expression in intratumoral iNKT cells and thereby diminishes their lipid synthesis and IFN-γ production. Activation of PPARγ via pioglitazone (PIO), a drug used to treat type 2 diabetes, restores lipid synthesis and IFN-γ production in those intratumoral iNKT cells, and significantly enhances anti-tumor efficacy of iNKT cell-based immunotherapy. Our results demonstrate the mechanisms underlying dysfunction of iNKT cells in tumor microenvironment, and provide important insights into interventions enhancing iNKT cell-mediated antitumor immune responses
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