Tumours express a variety of novel epitopes which represent potential immune targets, and thus clinically evident tumours are thought to have effectively avoided immune recognition and elimination. Transporters associated with antigen presentation (TAP) are thought to be responsible for conveying intracellular peptides into the endoplasmic reticulum for complex formation with class I MHC and subsequent recognition by cytotoxic T lymphocytes. In this study, we evaluated 79 human solid tumours and cell lines for genetic abnormalities in TAP1 that might have led to an acquired loss of antigen presenting ability. A novel sequence (R659Q) was discovered near the ATP binding site in a human small cell lung cancer (SCLC) cell line, H1436. This cell line is heterozygous for this allele, but only the R659Q allele is transcribed into RNA. Even though the R659Q protein is expressed, these cells act as if they were TAP deficient by peptide binding and antigen presentation studies, which are restored after transfection of a functional TAP1 allele. This is the first evidence for a naturally occuring protein structural defect resulting in defective peptide transport in a human solid tumour.