Although the immune system has the ability to reject tumors, this sometimes does not occur, leading to cancer. A group of specialized T cells, termed NKT cells, are powerful regulators of the first line of defense against some tumors and the subsequent development of adaptive (T and B cell) immune responses to these tumors. While NKT cells are naturally selected for reactivity with CD1d in the context of self glycolipids, it is not understood how NKT cells recognize and respond to tumor cells.
The aim of this project is to investigate the functional importance of NKT cells in either promoting or suppressing tumor immunity depending upon the context of the interactions that take place between NKT cells and antigen presenting cells (APC), including the nature of the glycolipid ligands that APC present to NKT cells. The applicants have characterized a series of unique mouse experimental tumor models to define the role of NKT cells. The marine sponge glycolipid alpha-galactosylceramide, activates NKT cells and reduces both tumor initiation and metastatic spread in mice. While this compound has entered phase I clinical trials in humans with advanced cancer, the mechanism of action of this glycolipid remains incompletely understood and the natural mammalian glycolipids that select for and regulate NKT cells remain undefined. Assessment of the biochemical composition of tumors that are recognized or ignored by NKT cells in mice, in conjunction with a variety of biochemical techniques will be used to isolate specific glycolipids that can stimulate anti-tumor immunity via NKT cells, with the promise of rationale design of a new class of adjuvants to promote T and NK cell responses to cancer. This proposal will also establish which subsets of NKT cells and APC either naturally promote or suppress tumor immunity. The importance of individual subsets of NKT cells and APC from various lymphoid organs will be tested by transferring these into mice that have been challenged with tumors and have specific deficiencies in all NKT cells or various APC subsets. Using other mice gene targeted for specific effector or regulatory molecules or neutralizing monoclonal antibodies, we will be able to dissect the molecular networks that control these processes between NKT cells and APC. This proposal focuses clearly on a pivotal immune control mechanism that will influence many current and future immunotherapies.
