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Open AccessArticle

Sphingosine Kinase Blockade Leads to Increased Natural Killer T Cell Responses to Mantle Cell Lymphoma

by Michael S. Lee 1,2, Wenji Sun 1,2 and Tonya J. Webb 1,2,*
1
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
2
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
*
Author to whom correspondence should be addressed.
Cells 2020, 9(4), 1030; https://doi.org/10.3390/cells9041030
Received: 21 January 2020 / Revised: 10 April 2020 / Accepted: 12 April 2020 / Published: 21 April 2020
(This article belongs to the Special Issue Sphingolipids in Cancer Progression and Therapy)
Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin’s lymphoma. Despite being responsive to combination chemotherapy, median survival remains around 5 years due to high rates of relapse. Sphingolipid metabolism regulates MCL survival and proliferation and we found that sphingosine-1-phosphate (S1P) is upregulated in MCL cells. Therapeutic targeting of the S1P1 receptor or knockdown of sphingosine kinase 1 (SK1), the enzyme responsible for generating S1P, in human MCL cells results in a significant increase in Natural Killer T (NKT) cell activation. NKT cells recognize glycolipid antigens presented on CD1d and can reduce MCL tumor burden in vivo. Lipidomic studies identified cardiolipin, which has been reported to bind to CD1d molecules, as being upregulated in SK1 knockdown cells. We found that the pretreatment of antigen presenting cells with cardiolipin leads to increased cytokine production by NKT cell hybridomas. Furthermore, the ability of cardiolipin to activate NKT cells was dependent on the structure of its acyl chains. Collectively, these studies delineate novel pathways important for immune recognition of malignant cells and could lead to the development of new treatments for lymphoma. View Full-Text
Keywords: Mantle cell lymphoma; NKT cells; sphingosine kinase; sphingosine-1-phosphate; cardiolipin Mantle cell lymphoma; NKT cells; sphingosine kinase; sphingosine-1-phosphate; cardiolipin
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Lee, M.S.; Sun, W.; Webb, T.J. Sphingosine Kinase Blockade Leads to Increased Natural Killer T Cell Responses to Mantle Cell Lymphoma. Cells 2020, 9, 1030.

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