Harnessing Invariant Natural Killer T Cells for Cancer Therapy

Abstract SCI-20

Natural killer T (NKT) cells are distinct innate lymphocytes that recognize lipid ligands in the context of nonclassical MHC molecules called CD1d. NKT cells have been broadly classified into two major types based on their T-cell receptors (TCRs). One group, termed type I invariant, or iNKT cells, bears a noncanonical conserved TCR (Va24/Vb11 in humans, and Va14 in mice), while others, termed type II NKT cells, express diverse TCRs. Recent studies have identified several naturally occurring lipid ligands recognized by these cells. iNKT cells are efficiently activated by α-galactosylceramide (α-GalCer), a lipid ligand first isolated from a marine sponge. Activation of iNKT cells in vivo leads to activation of NK cells, as well as downstream activation of adaptive immunity, leading to strong antitumor effects in mice. Several hematologic malignancies express CD1d and are attractive targets of NKT-targeted therapeutic approaches. Progression from premalignant gammopathy to clinical myeloma is associated with loss of the interferon-γ-secreting effector function of NKT cells. Adoptive transfer of α-GalCer-loaded dendritic cells (DCs) led to activation and expansion of circulating NKT cells in vivo in patients with advanced cancer. However, the functional properties of NKT cells were found to be impaired. Lenalidomide leads to enhanced activation and cytokine secretion by NKT cells in a ligand-dependent manner in culture. This led us to treat patients with early multiple myeloma with three cycles of low-dose lenalidomide and α-GalCer-loaded DCs. Preliminary studies from this trial show that this combination leads to activation of diverse innate cells, including NKT and NK cells, and upregulation of NKG2D and CD56. Activation of these innate lymphocytes also led to an increase in serum-soluble interleukin-2 receptor and induction of eosinophilia. Together, these data demonstrate the capacity of this combination to recruit several innate lymphocytes and mediate antitumor effects. In contrast to conventional MHC I/II restricted T cells, understanding the diversity and functional properties of lipid-reactive T cells is still in its infancy. The biology of NKT cells may have an impact, due to the cells' immune-regulatory properties, in diverse inflammatory states, including cancer, atherosclerosis, and allergy. This research was supported in part by funds from the Translational Research Program of the Leukemia and Lymphoma Society.