Mantle Cell Lymphoma induced reduction of human NKT cells (162.25)

Abstract

Abstract Natural killer T (NKT) cells are important in regulating immune responses against tumors. However, patients with mantle cell lymphoma (MCL), an aggressive subtype of Non-Hodgkins Lymphoma (NHL), have a reduction in both NKT cell number and function. We have found that NKT cells from MCL patients fail to be activated by autologous B cells, even in the presence of α-Galactosylceramide (α-GalCer), a potent activator of NKT cells. NKT cells from MCL patients had a significant reduction in their expansion potential and in cytokine production. Compared to serum from healthy donors, MCL serum induced chronic NKT cell stimulation and a rapid upregulation of PD-1 in cultured primary NKT cells (from healthy donors), resulting in an exhausted or anergic phenotype. Mass spectrometry demonstrated the presence of higher levels of sphingosine 1-phosphate (S1P) in patient sera compared to healthy controls sera. The functional involvement of S1P in NKT activation was supported by restoration of the anti-tumor function of NKT cells against MCL following S1P1 signaling blockade. These data suggest that tumor-related induction of S1P production and/or S1P signaling in MCL patients can inhibit NKT cell function, ultimately resulting in reduced anti-tumor responses.