Abstract
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.
Highlights
Mantle cell lymphoma (MCL) is characterized by its genetic hallmark, the chromosomal translocation t(11;14), which results in increased expression of cyclin D1 in B cells, alterations in the DNA damage response, and constitutive activation of key anti-apoptotic pathways, such as phosphatidyl-inositol 3-kinase (PI3K)/Akt and nuclear factor-kB (NF-kB) [1]
We found that the pretreatment of antigen presenting cells with cardiolipin leads to increased cytokine production by Natural Killer T (NKT) cell hybridomas
These data suggest that S1P inhibits the ability of the target cell to induce NKT cell activation and this pathway may contribute to failure of immune surveillance in MCL
Summary
Mantle cell lymphoma (MCL) is characterized by its genetic hallmark, the chromosomal translocation t(11;14), which results in increased expression of cyclin D1 in B cells, alterations in the DNA damage response, and constitutive activation of key anti-apoptotic pathways, such as phosphatidyl-inositol 3-kinase (PI3K)/Akt and nuclear factor-kB (NF-kB) [1]. These changes result in cell cycle dysregulation and give rise to profound genetic instability [2]. NKT cells have been demonstrated to play a role in autoimmune disease [7], tumor surveillance [6,8], hematological cancers [9], infectious disease, and inflammatory conditions such
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