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Sphingosine Kinase-2 Inhibition Increases Acetyl-CoA Carboxylase Activity and Phosphatidylcholine Levels to Program Immunogenicity in Myeloid-Derived Suppressor Cells [ATAC-seq]

ABSTRACT: Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) are a major barrier to adoptive T cell therapy, underscoring the need to enhance T cell efficacy by overcoming immunosuppression. Here, we investigated how sphingosine-1-phosphate (S1P), an abundant signaling lipid in the TME, regulates the programming and function of MDSCs. We show that inhibition of sphingosine kinase-2 (SphK2), which generates S1P in MDSCs, reduces their suppressive activity and enhances antigen presentation. Pharmacological inhibition of SphK2 improved the response to anti-PD1 therapy in preclinical models of checkpoint-resistant breast, bladder, and melanoma cancers by mitigating MDSCmediated suppression, thereby limiting tumor progression. Mechanistically, S1P directly interacts with Acetyl-CoA Carboxylase 1 (ACC1) to inhibit its activity, altering fatty acid and glycolytic pathways. Lowering intracellular S1P restores ACC activity and promotes phosphatidylcholine synthesis, reducing the immunosuppressive phenotype of MDSCs. These findings highlight the SphK2/ACC/phospholipid axis as a promising therapeutic target in cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE309615 | GEO | 2026/05/04

REPOSITORIES: GEO

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Sphingosine Kinase-2 Inhibition Increases Acetyl-CoA Carboxylase Activity and Phosphatidylcholine Levels to Program Immunogenicity in Myeloid-Derived Suppressor Cells [RNA-seq]

Project description:Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) are a major barrier to adoptive T cell therapy, underscoring the need to enhance T cell efficacy by overcoming immunosuppression. Here, we investigated how sphingosine-1-phosphate (S1P), an abundant signaling lipid in the TME, regulates the programming and function of MDSCs. We show that inhibition of sphingosine kinase-2 (SphK2), which generates S1P in MDSCs, reduces their suppressive activity and enhances antigen presentation. Pharmacological inhibition of SphK2 improved the response to anti-PD1 therapy in preclinical models of checkpoint-resistant breast, bladder, and melanoma cancers by mitigating MDSC- mediated suppression, thereby limiting tumor progression. Mechanistically, S1P directly interacts with Acetyl-CoA Carboxylase 1 (ACC1) to inhibit its activity, altering fatty acid and glycolytic pathways. Lowering intracellular S1P restores ACC activity and promotes phosphatidylcholine synthesis, reducing the immunosuppressive phenotype of MDSCs. These findings highlight the SphK2/ACC/phospholipid axis as a promising therapeutic target in cancer immunotherapy.

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Next Generation Sequencing Facilitates Quantitative Analysis of Wild Type, SphK1-/- and SphK2-/- fibroblasts Transcriptomes

Project description:In numerous forms of organ injury, interstitial fibrosis is a final common pathway. Despite recent epidemiological studies, therapies to focus on fibrosis and to delay progressive renal failure are limited. Previously our group showed that sphingosine kinase 2 deficient-mice (SphK2-/-) develop less fibrosis in folic acid-induced or unilateral ischemia-reperfusion injury (IRI)-induced kidney fibrosis models. Sphingosine 1-phosphate (S1P) is produced by two sphingosine kinase isoforms (SphK1 and SphK2). S1P is involved in diverse functions, but the role of S1P produced by SphK2 is gathering attention as treatments focused on epigenetics have been developed. SphK2 is primarily located in the nucleus and S1P produced by SphK2 inhibits histone deacetylase (HDAC) and changes in histone acetylation status, which can lead to an altered target gene expression. We identified that bone marrow stromal cell antigen-1 (Bst1/CD157) is a gene related with kidney fibrosis based on the combination of genome-wide analysis and in vivo screening. SphK2 regulates Bst1 expression and Bst1-/- mice develop less fibrosis after unilateral IRI and are protected against renal bilateral IRI. Bone marrow chimera experiments further revealed the importance of Bst1 expression on hematopoietic cells. Furthermore we identified the role of Bst1 expression in neutrophils for inducing renal ischemia-reperfusion injury and fibrosis.

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Acetyl-CoA Carboxylase Obstructs CD8+ T-Cell Lipid Utilization in the Tumor Microenvironment

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