期刊
CELLS
卷 9, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/cells9041030
关键词
Mantle cell lymphoma; NKT cells; sphingosine kinase; sphingosine-1-phosphate; cardiolipin
类别
资金
- National Institutes of Health [R21 CA162277, R21 CA199544, R21 CA184469]
- National Cancer Institute [P30CA134274]
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 S1P(1) 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.
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