Thursday, April 3, 2025
4/3/2025
Targeting S1P-ACC Axis to Overcome MDSC Suppression - ABSTRACT One of the key-confounding factors that hampers the adoptive T cell therapy is the presence of immunosuppressive cells like myeloid-derived suppressor cells (MDSCs), Tumor associated macrophages (TAMs) in the tumor microenvironment (TME). Thus, strategies to boost the anti-tumor T cell function in vivo by overcoming immunosuppression holds merit. In addressing the role of sphingolipids in TME we noted that MDSCs obtained from Sphingosine-kinase-2 knock-out (SphK2 KO) mice, and not SphK1 KO mice, had reduced immunosuppressive phenotype as evident from the increased proliferation and IFN-γ secretion by T cells co- cultured with SphK2 KO MDSCs. The reduced suppressive capacity of SphK2 KO MDSCs correlated to reduced expression of signature immunosuppressive molecules like Arginase, IDO, IL10, TGFβ whereas high levels of immunogenic cytokine IL12 compared to wild-type (WT) MDSCs. SphK2 KO MDSCs also exhibited upregulated expression of co-stimulatory molecules CD80, CD86, and MHC Class-I expression that correlated to the accumulation of fatty acids (FA) and enhanced activity of Acetyl CoA carboxylase (ACC), an enzyme that catalyzes conversion of acetyl CoA to malonyl CoA, a carbon donor for long chain FA synthesis. Since Acc1 is inactive when phosphorylated, we hypothesize that SphK2 mediated S1P regulates ACC activity, and its inhibition leads to increased fatty acid synthesis and immunogenic phenotype of the myeloid cells in the tumor microenvironment. Furthermore, inhibiting the MDSC suppressive function by pharmacological inhibition of SphK2 (using ABC294640) along with adoptive transfer of T cells and a checkpoint inhibitor (anti-PD1 antibody) improved the control of subcutaneously established B16-F10 melanoma. These observations have led us to propose the following specific aims for this project: 1) Determine how SphK2-mediated S1P induces MDSC suppressive phenotype, 2) Determine the mechanism of how SphK2-mediated S1P alters MDSC metabolism, and 3) Determine if SphK2 inhibition improves tumor control and enhances immunotherapy outcomes in vivo. These studies hold immense translational significance for patients with cancer where SphK2/S1P axis can be targeted to overcome immunosuppression and improve immunotherapeutic control of the tumors.
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