Sphingosine Kinase Blockade Leads to Increased Natural Killer T Cell Responses to Mantle Cell Lymphoma
MetadataShow full item record
AbstractMantle 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.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85084031103&doi=10.3390%2fcells9041030&partnerID=40&md5=89c4fa61d5d128bcee3d7284bf700392; http://hdl.handle.net/10713/12707
- TNF-α production in NKT cell hybridoma is regulated by sphingosine-1-phosphate: implications for inflammation in atherosclerosis.
- Authors: Ito S, Iwaki S, Kondo R, Satoh M, Iwabuchi K, Ohkawa R, Mishima Y, Yatomi Y, Furumoto T, Tsutsui H, Fujii S
- Issue date: 2014 Jun
- Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma.
- Authors: Tiper IV, Webb TJ
- Issue date: 2016 Nov
- FTY720, a sphingosine 1-phosphate receptor modulator, inhibits CD1d-restricted NKT cells by suppressing cytokine production but not migration.
- Authors: Hwang SJ, Kim JH, Kim HY, Kim S, Chung DH
- Issue date: 2010 Jan
- Structural basis of NKT cell inhibition using the T-cell receptor-blocking anti-CD1d antibody 1B1.
- Authors: Ying G, Wang J, Mallevaey T, Van Calenbergh S, Zajonc DM
- Issue date: 2019 Aug 30
- Alterations in cellular metabolism modulate CD1d-mediated NKT-cell responses.
- Authors: Webb TJ, Carey GB, East JE, Sun W, Bollino DR, Kimball AS, Brutkiewicz RR
- Issue date: 2016 Aug