Abstract

CD1d-restricted ´Natural Killer T´ cell (NKT) populations enhance anti-pathogen and anti-tumour immunity. NKT are required for optimal resistance to certain infections and presence of Th1-biased NKT cells is specifically associated with cancer patient survival. Patient NKT defects are reversible in vitro, so we are investigating their correction in models and the clinic (latter based on our NKT cell mAb). In the Tramp prostate cancer model, a tumour cell-based vaccine augmented by NKT stimulation was therapeutically active in advanced disease. NKT cell restoration in stage IV melanoma patients was well-tolerated with signs of immune activation. Progression-free survival of the majority of these highly-selected patients was over a year. There are further distinct NKT populations. Liver lymphocytes are dominated by NKT cells which can protect against acute infections, but their chronic stimulation can contribute to hepatitis. In human as well as murine bone marrow and adipose, NKT can suppress inflammation (e.g. Graft-versus-Host Disease and Type 2 Diabetes). NKT cells are highly enriched in adipose, but depleted in obesity. However, NKT can still protect against metabolic effects of obesity. Finally, where NKT cells are found to be refractory, CD1d mAbs, as well as blocking NKT :CD1d interaction, potently stimulate CD1d+ antigen-presenting cell maturation. We are working toward control of NKT cells in a range of diseases and vaccines.