Adoptive T cell therapy (ACT), which involves the isolation of antigen-specific T cells, followed by their ex vivo expansion and then infusion into autologous tumor bearing host, is a promising approach for treating patients with advanced malignancies. However, a number of confounding factors (as immunosuppression, cell death) exist that impair the long-lived T cell response. Thus, strategies to boost the anti-tumor T cell function in vivo holds merit. Given the role of sphingosine-1 phosphate (S1P) gradient in egress of T cells from thymus and recent reports that highlight the importance of S1P/S1PR in selectively activating Akt-mTOR kinase pathway to impede the development and function of suppressive regulatory T cells, we evaluated if altering sphingosine kinase (SK) mediated S1P may have benefits for anti-tumor T cell response. Two mammalian SKs, SK1 and SK2, that differ in localization (SK1 in cytoplasm and SK2 in nucleus) are key enzyme in sphingolipid metabolism that are involved in the production of S1P mediated control of many cellular responses such as cell proliferation, cell migration and cytokine production. Importantly, the role of SK1 or SK2 regulating in peripheral immune cells, and specifically if it can be exploited to improve immunotherapy has not been addressed. Thus, we initiated our preliminary studies using less explored SK2 deficient (SK2-/-) mice and found that myeloid derived suppressor cells (MDSCs) from SK2-/- tumor bearing mice exhibit reduced suppressive phenotype, which correlated to reduced activity of arginase-1, interleukin (IL)-10, STAT-3, and TGF-. In addition, tumor derived SK2-/- MDSCs also showed lower expression of hypoxia inducing factor (HIF)-1a, that is known to regulate MDSC suppressive function and glycolytic commitment. This leads us to hypothesize that sphingosine kinase-2/sphingosine-1 phosphate axis regulate the suppressive phenotype/function of tumor derived MDSCs, and targeting SK2/S1P pathway could enhance anti-tumor T cell function. We propose the following specific aims: 1) To determine the mechanism of SK2/S1P axis in regulating MDSC function; and, 2) To determine therapeutic potential of inhibiting SK2/S1P axis in controlling tumor growth. We believe that the results obtained from this study will identify novel targets for limiting immunosuppression in a tumor microenvironment, and will be of therapeutic significance in controlling tumor progression.
Understanding the mechanism of immunosuppression is key to improving the effectiveness of cytolytic T cells in adoptive T cell immunotherapy. Our preliminary data highlights a striking role for SK2 in down regulating the function of MDSCs. While this is novel, we propose here to understand the specific mechanism that SK2 deficiency targets for rendering MDSCs dysfunctional, and test if this strategy could be successfully combined with adoptive T cell therapy to achieve better tumor control.
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| Knochelmann, Hannah M; Smith, Aubrey S; Dwyer, Connor J et al. (2018) CAR T Cells in Solid Tumors: Blueprints for Building Effective Therapies. Front Immunol 9:1740 |
| Al-Hommrani, Mazen; Chakraborty, Paramita; Chatterjee, Shilpak et al. (2016) Dynamic Metabolism in Immune Response. J Immunol Res Ther 1:37-48 |
