Direct identification of human tumor-associated peptide antigens and a preclinical model to evaluate their use

Although the arsenal of a healthy immune system includes both circulating a ntibodies and cellular components such as T cells, the latter seem to be pa rticularly important in tumor immunology. Under normal conditions, the immu ne system does not react to the body's cells, which may be described as exp ressing "self" antigens on the cell surface. When a cell becomes cancerous, however, novel antigens are expressed on the cell surface. These novel "tu mor" antigens are recognized as foreign by the body's immune system, and th e cells that express them are destroyed or incapacitated. Whereas antibodies may react directly with protein antigens, T cells instea d recognize peptide antigens presented by class I and class II molecules of the major histocompatibility complex (MHC). All cells normally break down proteins that they have made. The class I antigen-processing pathway has ev olved to display peptides produced by this breakdown process as a way to pr ovide information to cytotoxic T cells about what the cell is making. The d isplay of new peptides as a result of infection or transformation can stimu late cytotoxic T cells to kill the cell. In addition, antigen-processing ce lls such as dendritic cells engulf dead or dying cells and degrade proteins into peptide fragments. These peptides are then displayed by the MHC class II molecules and presented to T helper cells, which augment the activity o f the cytotoxic T cells. Cytotoxic T lymphocytes have recently been isolated from human tumors (espe cially melanoma) and are critical to the development of promising immunothe rapeutic agents. As we shall discuss, these cells can recognize antigens th at are common to tumors from different patients. The shall also explore how advances in instrumentation and the use of transgenic mice have increased our understanding of tumor-associated peptides to the point where we can be gin to strive for a peptide-based therapeutic vaccine. The caveats for such therapy will also be addressed.