Insights into the processing of MHC class I ligands gained from the study of human tumor epitopes

The molecular definition of tumor antigens recognized by cytolytic T lymphocytes (CTL) started in the late 1980s, at a time when the MHC class I antigen processing field was in its infancy. Born together, these two fields of science evolved together and provided each other with critical insights. Over the years, stimulated by the potential interest of tumor antigens for cancer immunotherapy, scientists have identified and characterized numerous antigens recognized by CTL on human tumors. These studies have provided a wealth of information relevant to the mode of production of antigenic peptides presented by MHC class I molecules. A number of tumor antigenic peptides were found to result from unusual mechanisms occurring at the level of transcription, translation or processing. Although many of these mechanisms occur in the cell at very low level, they are relevant to the immune system as they determine the killing of tumor cells by CTL, which are sensitive to low levels of peptide/MHC complexes. Moreover, these unusual mechanisms were found to occur not only in tumor cells but also in normal cells. Thereby, the study of tumor antigens has illuminated many aspects of MHC class I processing. We review here those insights into the MHC I antigen processing pathway that result from the characterization of human tumor antigens recognized by CTL