Identification of Novel and Widely Expressed Cancer/Testis Gene Isoforms That Elicit Spontaneous Cytotoxic T-Lymphocyte Reactivity to Melanoma

Abstract

Multiple isoforms (TAG-1, TAG-2a, TAG-2b, and TAG-2c) of a novel cancer/testis antigen gene have been identified and are expressed in 84 -88% of melanoma cell lines tested. The tumor antigen (TAG) genes are also expressed in K562, a myelogenous leukemia cell line, and they have homology to two chronic myelogenous leukemia-derived clones and a hepatocellular carcinoma clone in the human expressed sequence tags (EST) database, thus indicating that their expression is not restricted to melanomas. In contrast to the fact that many cancer/testis antigens are poorly immunogenic, the TAG-derived peptide, RLSNRLLLR, is recognized by HLA-A3-restricted, melanoma-specific CTLs that were obtained from a melanoma patient with spontaneous reactivity to the peptide. Unlike most cancer/testis antigen genes which are located on the X chromosome, the TAG genes are located on chromosome 5. The genes have the additional unusual features of being coded for in an open reading frame that is initiated by one of three nonstandard initiation codons, and the sequence coding the RLSNRLLLR peptide crosses an exon-exon boundary. The properties of the TAG antigens indicate that they are excellent vaccine candidates for the treatment of melanoma and perhaps other cancers.

The contributions of mass spectrometry to understanding of immune recognition by T lymphocytes

“…This approach has been used to identify a large number of individual peptide antigens that are presented by class I MHC molecules and recognized by CD8 T cells. These include: transplantation antigens recognized by T cells during the course of tissue graft rejection and graft versus host disease [26,[49][50][51][52][53][54][55][56][57]; antigens expressed on melanoma [43,[58][59][60], lung carcinoma [61], colon carcinoma [62], breast and other epithelial carcinomas [63], and UV-induced sarcoma [64]; antigens derived from intracellular bacteria [65,66]; and antigens recognized during the development of autoimmune diabetes [67]. A similar approach has enabled the identification of peptide antigens presented by class II MHC molecules and recognized by CD4 T cells [68].…”

“…Among these, O-linked glycosylation of Lys [129], N-linked glycosylation of Asn [124,130], N-terminal acetylation [131], methylation of Arg [130], and phosphorylation of Ser and Thr [61,129] have all been identified through the use of mass spectrometry. Hunt and colleagues have also identified several peptides containing cysteine residues that have been altered by the attachment of another cysteine residue via a disulfide bond [53,132,133].…”

“…This category of modified MHC-associated peptides is of particular interest. They may represent important antigens displayed on infected cells as a consequence of inflammatory reactions [139,140], or may create new targets for immune recognition of cancer cells [61,129,141,142]. They have been shown to be involved in the development of autoimmune diseases [143].…”

Vacuna idiotípica en el tratamiento del linfoma folicular: situación actual y perspectivas futuras

“…Todas estas alteraciones darían lugar a un potencial Ag específico de tumor. De hecho, se han detectado respuestas inmunológicas específicas contra algunos determinantes antigénicos derivados de proteínas con splicing anóma-lo en pacientes con cáncer [49][50][51][52][53][54][55][56][57][58] .…”

Identification and Characterization of Ovarian Carcinoma Peptide Epitopes Recognized by Cytotoxic T Lymphocytes

“…The TAG genes were previously shown to be expressed in a large percentage of melanoma cell lines (21). To determine if the TAG genes are expressed in other cancers, a broad survey was taken using established tumor lines of non-melanocytic origin.…”