No abstract

Adoptive T cell transfer (ACT) holds promise in cancer therapy, and strategies to further improve its efficacy are being tested. It is reported that sphingosine 1-phosphate (S1P), generated by sphingosine kinase 1 (SphK1), regulates lymphocyte egress into circulation and also plays role in the differentiation of regulatory T cells and T helper-17 cells. Here, we examined the roles of SphK1/S1P signalling in regulating antitumor potential of T cells. We found that adoptive transfer of melanoma epitope gp100 reactive CD8 T cells (pMel) with SphK1 deficiency showed improved tumor control in murine melanoma model. Our data also indicated that Sphk1−/− T cells exhibited enhanced central memory phenotype, higher mitochondrial respiration and resistance to TGF-β mediated suppression. Importantly, Sphk1−/− T cells spontaneously secreted higher levels of IL17 compared to their wild type counterparts. Mechanistically, we demonstrate that SphK1/S1P signaling regulates IL17 generation through attenuation of PPARγ, which is down-regulated in Sphk1−/− T cells. In reciprocal studies, addition of S1P in culture media enhanced PPARγ expression, resulting in decreased IL17 production in Sphk1−/− T cells. Furthermore, down-regulation of PPARγ in Sphk1−/− T cell increased lipolysis to produce free fatty acids and metabolically reprogram T cells to depend on mitochondrial metabolism for meeting their energy demand. Thus, our data reveal that SphK1/S1P signaling regulates anti-tumor functions and persistence of T cells by controlling T cell energy metabolism through induction of lipolysis via PPARγ modulation. Overall, these data highlight the clinical potential of targeting SphK/S1P axis for improving efficacy of ACT for solid tumors.