Selective MHC expression in tumours modulates adaptive and innate antitumour responses

Progress towards developing vaccines that can stimulate an immune response against growing tumours has involved the identification of the protein anti gens associated with a given tumour type. Epitope mapping of tumour antigen s for HLA class I- and class II-restricted binding motifs followed by immun ization with these peptides has induced protective immunity in murine model s against cancers expressing the antigen. MHC class I molecules presenting the appropriate peptides are necessary to provide the specific signals for recognition and killing by cytotoxic T cells (CTL). The principle mechanism of tumour escape is the loss, downregulation or alteration of HLA profiles that may render the target cell resistant to CTL lysis, even if the cell e xpresses the appropriate tumour antigen. In human tumours HLA loss may be a s high as 50%, inferring that a reduction in protein levels might offer a s urvival advantage to the tumour cells. Alternatively, MHC loss may render t umour cells susceptible to natural killer cell-mediated lysis because they are known to act as ligands for killer inhibitory receptors (KIRs). We revi ew the molecular features of MHC class I and class II antigens and discuss how surface MHC expression may be regulated upon cellular transformation. I n addition, selective loss of MHC molecules may alter target tumour cell su sceptibility to lymphocyte killing. The development of clinical immunothera py will need to consider not only the expression of relevant CTL target MHC proteins, but also HLA inhibitory to NK and T cells.