Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin’s lymphoma, which encompasses a group of cancers derived primarily from B cells that have been increasing in incidence over the past 30 years.  Despite being initially responsive to combination chemotherapy, median survival remains around 5 years due to high rates of relapse.  Natural Killer T (NKT) cells play an important role in cancer surveillance and can reduce MCL tumor burden in vivo; however, NKT cells are reduced in number and function in MCL patients compared to healthy donors.  Sphingolipid metabolism plays an important role in regulating MCL survival and proliferation. We found that sphingosine-1-phosphate (S1P) is upregulated in MCL cells.  Knockdown of sphingosine kinase 1 (SK1), the enzyme responsible for generating S1P, in human MCL cells results in a significant increase in CD1d-mediated NKT cell activation, as assessed by cytokine production and cytotoxicity. Lipidomic studies identified cardiolipin as being upregulated in SK1 knockdown cells. Cardiolipin has been reported to bind to CD1d molecules.  Thus, to test if cardiolipin could induce NKT cell activation, we pulsed antigen-presenting cells with cardiolipin and then co-cultured the cells with a panel of NKT cell hybridomas.  We found that pretreatment with cardiolipin leads to increased cytokine production by NKT hybridomas. Cardiolipin is typically sequestered in the mitochondrion; therefore, future studies will focus on identifying factors required for CD1d-mediated processing and presentation of cardiolipin.  Collectively, these studies will delineate novel pathways important for immune recognition of malignant cells and could lead to the development of new treatments for lymphoma.