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"Aberrant transcript of W-acetylglucosaminyl transferase V (GnTV) that is found only in melanomas (50%). Encyclopedia of Immunology

"Aberrant transcript of W-acetylglucosaminyl transferase V (GnTV) that is found only in melanomas (50%). Encyclopedia of Immunology significant expression of these genes was detected are testicular germ cells and placental trophoblasts. Since these cells do not express MHC Class I molecules, they do not present the peptide at their surface. Therefore such antigens can be considered as strictly tumor specific. The activation of the genes usually results from a demethylation of their promoter that correlates with a nonspecific genome-wide demethylation. Expression was detected in substantial fractions of human melanomas, head and neck, lung, bladder and breast carcinomas (Table 2). Because they are shared by tumors expressing the genes and bearing the approporiate MHC type, these antigens represent promising targets for cancer immunotherapy. About 60% of melanomas, 40% of head and neck tumors, 34% of non-small cell lung carcinomas and 28% of bladder tumors express at least one of the antigens identified to date.

Some CTLs-directed against breast, ovarian and pancreatic carcinomas recognize an epitope of mucin, a surface protein composed of multiple tandem repeats of 20 amino acids. Whereas in normal cells mucin is heavily glycosylated, in these tumors the peptide repeats are unmasked by underglycosyl-ation, resulting in CTL recognition. Remarkably, this recognition, which depends on the presence of multiple repeats, occurs in the absence of HLA restriction. Mucin underglycosylation also occurs in breast duct epithelial cells during lactation, but only at the extracellular apical surface which normally is not accessible to T cells. These mucin antigens therefore appear to be very specific for tumor cells, and the lack of HLA restriction should facilitate therapeutic vaccination trials.

Lymphocytes infiltrating some HLA-A2 ' ovarian carcinomas were found to recognize peptides derived from HER-2/neu, an oncogene expressed in normal tissues at low levels and overexpressed in 30% of breast and ovarian carcinomas.

Differentiation antigens

A large number of CTLs directed against human melanoma were found to recognize not only a majority of HLA-A2 melanomas but also HI..A-A2 ' normal melanocytes. The notion that such CTLs recognize melanocyte differentiation antigens was confirmed when the antigens were identified at the molecular level. Five genes encoding melanocyte differentiation antigens have been identified (Table 3). Most antigenic peptides are presented by HLA-A2, but other HLA-peptide combinations have been found. Two tyrosinase peptides are presented by HLA-DR4 to CD4 T cells. The gp75 peptide presented by HLA-A31 is peculiar in that it is translated from an open reading frame that is different from the one encoding the gp7.5 protein. Tyrosinase peptide 369-377 presents an interesting post-trans-lational modification that was observed when the naturally occurring peptide eluted from an HI.A-A2 melanoma was analyzed (Table 3). The asparagine residue in position 3 is transformed into an aspartic acid residue, presumably because the asparagine was glycosylated and subsequently deglycosylated by an enzyme which removed the amino group with the glycan.

The role of CTLs against such antigens in melanoma rejection is not clear, but is supported by the reported association of vitiligo with prolonged survival and spontaneous regression of melanoma. Because melanocytes are also present in the choroid layer of retina, the potential ophthalmic toxicity of active immunotherapy targeted at these antigens needs to be evaluated.

Similar concerns about autoimmune side-effects

Table 2 Expression in tumor samples of genes encoding T cell antigens"

Histological type

Percentage of tumors expressing:

Table 2 Expression in tumor samples of genes encoding T cell antigens"

Histological type

Percentage of tumors expressing:

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