Sphingosine kinase 1 and its role in modulation of anti-tumor T-cell responses (VAC3P.951)

Abstract

Abstract Sphingosine kinase 1(Sphk1) is a key enzyme in sphingolipid metabolism that is involved in the production of sphingosine-1-phosphate (S1P). S1P controls many cellular processes such as cell proliferation, migration and cytokine production. We sought to address the role of Sphk1 in regulating T cell responses to a tumor specific ‘self’ antigen gp100, in a mouse model of melanoma by generating TCR transgenic mice pMel on Sphk1 deficient background. We found that Sphk1-/-pMel mice showed reduced tumor progression on subcutaneous administration of B16-melanoma. Tumor progression was slower when T-cells from Sphk1-/-pMel mice were adoptively transferred to treat Rag-/- mice with established subcutaneous tumors. There was an increased infiltration of Sphk1-/-pMel T-cells at the tumor site as compared to pMel cells. This suggests that loss of Sphk1 from T-cells enhanced their ability to target the tumor site. We also found TGF-β mediated suppression of IFN-γ secretion was poorer in Sphk1-/- T-cells suggesting better functionality of effector T cells infiltrating the tumor site. A comparative evaluation of T cells from WT and Sphk1-/-pMel showed similar cell surface markers, activation status and proliferation and Tc1 cytokine response. However, we found that Sphk1-/- T-cells showed greater IL-17 secretion. It is possible that the enhanced anti-tumor T cell immunity noticed in Sphk1-/- mice is dependent on the innate Tc17 phenotype and lesser susceptibility to suppression.