NKT Cell Responses to B Cell Lymphoma

Abstract

Natural killer T (NKT) cells are a unique subset of CD1d-restricted T lymphocytes that express characteristics of both T cells and natural killer cells. NKT cells mediate tumor immune-surveillance; however, NKT cells are numerically reduced and functionally impaired in lymphoma patients. Many hematologic malignancies express CD1d molecules and co-stimulatory proteins needed to induce anti-tumor immunity by NKT cells, yet most tumors are poorly immunogenic. In this study, we sought to investigate NKT cell responses to B cell lymphoma. In the presence of exogenous antigen, both mouse and human NKT cell lines produce cytokines following stimulation by B cell lymphoma lines. NKT cell populations were examined ex vivo in mouse models of spontaneous B cell lymphoma, and it was found that during early stages, NKT cell responses were enhanced in lymphoma-bearing animals compared to disease-free animals. In contrast, in lymphoma-bearing animals with splenomegaly and lymphadenopathy, NKT cells were functionally impaired. In a mouse model of blastoid variant mantle cell lymphoma, treatment of tumor-bearing mice with a potent NKT cell agonist, α-galactosylceramide (α-GalCer), resulted in a significant decrease in disease pathology. Ex vivo studies demonstrated that NKT cells from α-GalCer treated mice produced IFN-γ following α-GalCer restimulation, unlike NKT cells from vehicle-control treated mice. These data demonstrate an important role for NKT cells in the immune response to an aggressive hematologic malignancy like mantle cell lymphoma.

Role and Regulation of CD1d in Normal and Pathological B Cells

“…Numerous pre-clinical studies have demonstrated the power of the CD1d-iNKT cell axis to enhance (or in some cases inhibit) anti-tumour immunity (57). iNKT cells can directly target CD1d-expressing tumours (mostly of haematological, including lymphoid origin) (58, 59), or indirectly, by activating adaptive and innate immune responses that can secondarily target CD1d- tumours (mostly of epithelial origin). Here we will restrict discussion to the evidence linking the CD1d-iNKT cell axis to the biology and clinical behaviour of mature B lineage malignancies, in particular MM and chronic lymphocytic leukaemia (CLL), two of the most common haematological malignancies.…”

Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma

“…NKT cells have a well-established role in mediating anti-tumor responses [5, 10]. However, studies from our lab and others have shown that NKT cells are physically and functionally reduced in cancer patients [11-13], which suggests that tumors may utilize various mechanisms to evade NKT cell-mediated immune surveillance.…”

Sphingosine Kinase Blockade Leads to Increased Natural Killer T Cell Responses to Mantle Cell Lymphoma

“…α-Galactosylceramide (α-GalCer) is a potent activator of NKT cells [13,14], and following treatment with α-GalCer, NKT cells produce cytokines, undergo clonal expansion, and subsequently activate other immune cells [15][16][17][18][19]. After activation, human NKT cells can exhibit strong anti-tumor activity against many tumors [20,21]. Several groups have conducted clinical trials evaluating the effectiveness of α-GalCer as a potential therapeutic immunomodulator of NKT cells that yielded modest results, potentially due to a reduction in NKT cell number and function in cancer patients [22][23][24][25][26][27].Sphingosine-1-phosphate (S1P) regulates proliferation, survival, and migration of mammalian cells through both extracellular receptor-mediated and intracellular mechanisms [28][29][30].…”