Human tumor antigens recognized by T lymphocytes

W e have come a long way since the identification of the first human tumor antigen recognized by autologous CTL. This report provides a brief appraisal of these antigens and their potential for cancer immunotherapy. Our comments will be restricted to nonviral antigens. The initial work carried out on mouse tumors revealed two possible mechanisms for generating new antigens that might be suflficiendy tumor-specific to be of relevance to immunotherapy. The first mechanism involved a point mutation, and the second involved the transcriptional activation o fa gene not expressed in normal tissues (1-3). Subsequent work on mouse tumors provided two interesting examples of tumor antigens resulting from point mutations (4, 5). Tumor-specific Shared Antigens. Three families of genes that appear to code for highly specific tumor antigens have been identified so far, namely, the MAGE, BAGE, and GAGE genes (6-9). These genes are frequently expressed in a wide range of tumor types such as melanoma, lung carcinoma, sarcoma, and bladder carcinoma, but very rarely in other tumor types such as brain tumors, renal carcinoma, and leukemia (7, 10-12). The only normal tissues where expression of these genes has been observed are testis and placenta (7). Starting from CTL clones obtained by stimulating lymphocytes with an autologous melanoma cell line, six antigens encoded by MAGE-1, MAGE-3, BAGE, and GAGE have been identified (8, 9, 13-15). For these six antigens, both the presenting HLA molecule and the antigenic peptide have been completely defined. Remarkably, all the relevant CTL were derived from the same melanoma patient, a patient with metastatic disease who enjoyed an extraordinarily favorable chnical course. Blood samples from several patients with a tumor expressing some or all of these genes were tested, and no such CTL were obtained by stimulating the lymphocytes with autologous tumor cells. More than 60% of Caucasian melanoma patients bear one of the presently defined antigens encoded by MAGE, BAGE, and GAGE. For other cancers such as head and neck tumors and bladder cancer, the frequencies range from 40% to 28%. For several reasons, it appears increasingly unlikely that immunization of patients against one of these antigens will cause harmful immunological side effects caused by the expression of the relevant gene in the testis. First, this expression appears to occur in germline cells, more precisely spermatocytes and spermatogonia (16). A similar observation has been made with the mouse equivalent of a MAGE gene by in situ hybridization (17). Because these germline cells do not express classical M H C class I molecules, gene expression should not result in antigen expression (18). These conclusions are further strengthened by immunization studies carried out with mouse tumor antigen P815A, which is encoded by a gene that is also expressed only in the testis. After immunization with P815 tumor cells, which carry this antigen, male mice produced a strong CTL response. No inflammation of the testis was observed in the following months, and the fertihty of these mice was normal (Uyttenhove, C., manuscript in preparation). A new mode of origin for antigens that are also tumorspecific shared antigens is described in this issue (19). Here, it seems that a gene that is ubiquitously expressed, namely, N-acetyl-glucosaminyltransferase V, contains an intron that appears to carry near its end a promoter that is activated only in melanoma cells. This atypical activation occurs in >50% of melanomas. This produces a message containing a new open reading frame, which codes for the antigenic peptide in its intronic part. Some CTL directed against breast, ovarian, and pancreatic carcinomas recognize an epitope of mucin, a surface protein composed of multiple tandem repeats of 20 amino acids (20-23). Whereas in normal cells mucin is heavily glycosylated, in these tumors the peptide repeats are unmasked by underglycosylation, resulting in CTL recognition. Remarkably, this recognition, which depends on the presence of multiple repeats, occurs in the absence of HLA restriction. The presence of this epitope was recently reported on myeloma cells, and mucin-specific CTL were isolated from the blood of a myeloma patient (24). These mucin antigens appear to be very specific for tumor cells, and the lack of HLA restriction should facilitate therapeutic vaccination trials. Differentiation Antigens. The observation that autolognus CTL can be generated readily against differentiation antigens present on normal melanocytes as well as melanoma cells was unexpected. Four genes encoding melanoma differentiation antigens have been identified: tyrosinase, Melan-A/Mart-1, gpl00, and gp75 (25-30). Most of the identified antigenic peptides are presented by HLA-A2, but other HLA-peptide combinations have been found (29-38). One tyrosinase peptide is presented by HLA-DR4 to CD4 T cells (34). The pattern of CTL precursors directed against these dif-