Therapeutic Approaches Utilising NKT Cells
Natural killer T (NKT) cells are members of the immune armamentarium with profound immunoregulatory effects. They bridge the innate and adaptive immune systems, filling a niche in recognizing glycolipid antigens, and responding rapidly to prime subsequent immune responses. In cancer, type I NKT cells, defined by their semi-invariant T cell receptor (TCR) using Vα14Jα18 in mice and Vα24Jα18 in humans, are mostly host protective, by producing interferon-γ (IFN-γ) to activate and mature dendritic cells (DC) to make IL-12, which in turn activates NK and CD8+ T cells. In contrast, type II NKT cells, characterized by more diverse TCRs recognizing lipids presented by CD1d, primarily inhibited anti-tumor immunity. This chapter will discuss the impact of CD1d-restricted NKT cells in tumor immune surveillance and immunotherapy and highlight recent therapeutic approaches in tumor mouse models with a focus on harnessing the anti-tumor activities of NKT cells.
KeywordsToxicity Lymphoma Adenocarcinoma Sarcoma Myeloma
SRM was supported by a Balzan Foundation Post-doctoral Fellowship. MJS was supported by a National Health and Medical Research Council of Australia (NH&MRC) Australia Fellowship.
- Fujii, S., Shimizu, K., Smith, C., et al. (2003b). Activation of natural killer T cells by alpha-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein. J Exp Med 198(2): 267–79.PubMedCrossRefGoogle Scholar
- Petersen, T. R., Sika-Paotonu, D., Knight, D. A., et al. (2010). Potent anti-tumor responses to immunization with dendritic cells loaded with tumor tissue and an NKT cell ligand. Immunol Cell Biol doi: 10.1038/icb.2010.9.
- Sfondrini, L., Besusso, D., Zoia, M. T., et al. (2002). Absence of the CD1 molecule up-regulates antitumor activity induced by CpG oligodeoxynucleotides in mice. Journal of Immunology 169(1): 151–58.Google Scholar
- Shin, Y., Hong, C., Lee, H., et al. (2010). NKT Cell-Dependent Regulation of Secondary Antigen-Specific, Conventional CD4+ T Cell Immune Responses. J Immunol doi: 10.4049/jimmunol.0903121.
- Terabe, M., Khanna, C., Bose, S., et al. (2006). CD1d-restricted natural killer T cells can down-regulate tumor immunosurveillance independent of interleukin-4 receptor-signal transducer and activator of transcription 6 or transforming growth factor-beta. Cancer Res 66(7): 3869–75.PubMedCrossRefGoogle Scholar
- Toura, I., Kawano, T., Akutsu, Y., et al. (1999). Cutting edge: Inhibition of experimental tumor metastasis by dendritic cells pulsed with alpha-galactosylceramide. Journal of Immunology 163(5): 2387–91.Google Scholar
- van der Vliet, H. J. J., Nishi, N., Koezuka, Y., et al. (2001b). Potent expansion of human natural killer T cells using alpha-galactosylceramide (KRN7000)-loaded monocyte-derived dendritic cells, cultured in the presence of IL-7 and IL-15. Journal of Immunological Methods 247(1–2): 61–72.PubMedCrossRefGoogle Scholar