S1P transporter SPNS2 expression modulates T cell immune response 4732

Abstract Description The bioactive lysophospholipid sphingosine-1-phosphate (S1P) is critical for lymphocyte trafficking and functions via the S1P-S1PR1 axis, but the impact of intracellular S1P levels on CD4+ T cell functions remain unclear. This study investigates the S1P transporter SPNS2 in regulating cytotoxic CD4+ T cells through S1P accumulation. CD4+ T cells from SPNS2 knockout (KO) mice exhibited an increased effector population with a cytotoxic phenotype, marked by elevated immune receptor activity and cytokine expression. Polarization toward the Th1 phenotype was significantly enhanced, as shown by increased T-bet and IFN-γ expression, an effect further amplified by SPNS2 inhibition (SLF1081851). SPNS2 KO CD4+ T cells displayed significantly elevated mitochondrial oxygen consumption rates (OCR), reflecting increased oxidative phosphorylation (OXPHOS), and RNA-seq analysis revealed upregulation of lipid metabolism pathways, aligning with their heightened functionality. In the B16-F10 melanoma model, SPNS2 KO mice demonstrated delayed tumor progression and improved survival. Tumor-infiltrating lymphocytes (TILs) from KO mice showed elevated activation markers and proinflammatory cytokines (IFN-γ, TNF-α), underscoring enhanced anti-tumor activity. These findings suggest that targeting SPNS2-mediated S1P metabolism in CD4+ T cells offers a promising strategy for cancer immunotherapy. Funding Sources Supported by NIH R01 CA250458; R01 CA236379; RO1 DE030013; R41 CA271958; R01CA282408-01A1; 2R42CA239952-02 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)