The tumor-rejection antigens of the 1591 ultraviolet fibrosarcoma. Potential origin and evolutionary implications (original) (raw)
Related papers
Journal of Experimental Medicine, 1986
The UV-induced, C3H fibrosarcoma, 1591, expresses at least three unique MHC class I antigens not found on normal C3H tissue. Here we report the complete DNA sequence of the three novel class I genes encoding these molecules, and describe in detail the recognition of the individual products by tumor-reactive and allospecific CTL. Remarkably, although C3H does not appear to express H-2L locus information, this C3H tumor expresses two distinct antigens, termed A149 and A166, which are extremely homologous to each other and to the H-2Ld antigen from BALB/c. The gene encoding the third novel class I antigen from 1591, A216, is quite homologous to H-2Kk) throughout its 3' end. Since all three of these genes account for polymorphic restriction fragments not found in C3H, it is likely that they were derived by recombination from the endogenous class I genes of C3H. The DNA sequence homology of A149, A166, and H-2Ld is especially significant given the functional conservation observed bet...
Proceedings of the National Academy of Sciences, 1985
Cancers induced by physical or chemical carcinogens express tumor-specific antigens that are uniquely specific for any given tumor; therefore, there is a seemingly endless variety of these unique antigens. We have studied a UV-induced fibrosarcoma, designated 1591, to elucidate the obscure molecular nature and genetic origins of unique tumor-specific antigens. A monoclonal antibody raised against syngeneic 1591 tumor cells has unique tumor specificity. This tumor-specific monoclonal antibody precipitated from the tumor a 45-kDa molecule associated with a 12-kDa molecule having the pI of beta2-microglobulin. This and other evidence indicated that the 1591 tumor expresses a novel class I molecule. A 1591 variant selected for the absence of binding to the monoclonal antibody lacked the novel class I MHC molecule as well as reactivity with cytotoxic T lymphocytes specific for the 1591 tumor. Furthermore, tumor cells bearing the antigen are rejected while variants that have lost the anti...
International Journal of Cancer, 1980
The fibrosarcoma ST2, induced by 3-methylcholanthrene in BALBlc (H-23 mice, also expressed alien histocompatibility antigens of the C3Hf and BIO background not encoded by the MHC. To examine the relationship between these alien, minor antigens and the tumor-specific transplantation antigen (TSTA) of the tumor, in vivo immunogenicity test were performed in BALB/c mice and in hybrids between BALBlc and C3Hf 2*), BIO.BR (H-2*), and BIO.DZ (H-23 mice. A significant loss of TSTA immunogenicity was found in (BALBl c X C3H9 and in (BALBlc X C3H.0H)Fl animals and, to a lesser extent, in (BALBlc X C3H.SW)Fl mice as compared t o the immunogenicity of the tumor in BALBlc mice. lmmunogenicity tests with ST2 in BALBlc X (BALBlc X C3H9 or in BALBlc X (BALBlc X BI0.DZ) backcross mice, respectively, revealed that half of the BALBlc X (BALBlc X C3Hf) and 97% of the BALBlc X (BALBlc X BIO.D2) animals were able t o mount an immune response to ST2. To see whether the loss of TSTA immunogenicity in (BALBlc X C3Hf) was due to common determinants shared between TSTA and alien non-H-2 C3Hf antigens or to a genetically linked low responsiveness to TSTA introduced by C3Hf and C3H.OH strains, BALBlc mice were immunized with normal normal tissues of some BALBk X (BALBlc X C3Hf) backcross, anti-ST2 resistant mice. Normal tissues of anti-ST2 resistant, ddand dktyped backcrosses were able to immunize BALBlc mice against a challenge of an otherwise lethal dose of ST2 cells. Some but not all BALBk X (BALBlc X BIO.DZ) anti-ST2 resistant donors had tissues able to immunize BALBlc hosts against the ST2 growth. Since resistance to tumor growth and expression of minor "alien" antigens shared with the tumor segregate independently, we concluded that alien, minor C3Hf and BIO antigens of the BALBlc sarcoma ST2 are distinct from the TSTA of this tumor.
5'-STRUCTURAL Analysis of Genes Encoding Polymorphic Antigens of Chemically Induced Tumors
Proceedings of the National Academy of Sciences, 1987
We have proposed that the distinct tumor rejection antigens of chemically induced sarcomas in inbred mice belong to a family of Mr 96,000 glycoproteins (gp96). An identical 14-amino acid sequence was found at the amino terminus of gp96 from two antigenically distinct BALB/c sarcomas. Oligonucleotide probes derived from this sequence permitted isolation of 5' cDNA and genomic fragments coding for gp96. Three short exons interrupted by relatively long introns were identified at the 5' terminus of the gp96 gene. The first exon encodes a signal peptide, which is consistent with gp96 being a cell surface antigen. Southern blot analysis indicated that the gp96 family is encoded by a single gene, and 3-kilobase transcripts were detected in all normal and tumor cells tested. Nucleotide and deduced amino acid sequences from 311 base paris at the 5' terminus showed no homology with any known protein. The availability of molecular probes for the gp96 system permits analysis of the ...
Journal of Experimental Medicine, 1997
The genetic origins of CD8+ T cell–recognized unique antigens to which mice respond when immunized with syngeneic tumor cells are unknown. The ultraviolet light-induced murine tumor 8101 expresses an H-2Kb-restricted immunodominant antigen, A, that induces cytolytic CD8+ T cells in vivo A+ 8101 cells are rejected by naive mice while A− 8101 tumor cells grow. To identify the antigen H-2Kb molecules were immunoprecipitated from A+ 8101 cells and peptides were eluted by acid. The sensitizing peptide was isolated by sequential reverse-phase HPLC and sequenced using microcapillary HPLC-triple quadruple mass spectrometry. The peptide, SNFVFAGI, matched the sequence of the DEAD box protein p68 RNA helicase except for a single amino acid substitution, caused by a single nucleotide change. This mutation was somatic since fibroblasts from the mouse of tumor origin expressed the wild-type sequence. The amino acid substitution created an anchor for binding of the mutant peptide to H-2Kb. Our re...
Identification of a human homologue of the murine tumor rejection antigen GP96
Cancer research, 1989
A family of cell surface glycoproteins with a molecular weight of 96,000 (gp96) has recently been implicated in the individually distinct immunogenicity of chemically induced sarcomas of inbred mice. Rabbit antiserum to murine gp96 detects an antigenically related Mr 96,000 cell surface glycoprotein on two cultured human melanoma cell lines, SK-MEL-13 and SK-MEL-177. Molecular probes for 5' and 3' ends of the murine gp96 gene detect a 3.5-kilobase transcript in RNA preparations from melanoma cells, similar to the murine gp96 transcript. While 5' probes do not hybridize to Southern blots of genomic human DNA, the 3' probes identify several distinct bands under stringent hybridization and washing conditions. This suggests that the 3' end of the gp96 gene is more conserved than its 5' end. No gross alterations in gp96 gene organization were detected in melanoma cells. B-lymphoblastoid cell lines derived from four different individuals also showed no restriction ...
Identification on a Human Sarcoma of Two New Genes with Tumor-specific Expression1
Cancer Research, 2000
Genes MAGE, BAGE, GAGE, and LAGE-1/NY-ESO-1 code for antigens that are recognized on melanoma cells by autologous CTLs. Because the pattern of expression of these genes results in the presence of antigens on many tumors of various histological types and not on normal tissues, these antigens qualify for cancer immunotherapy. To identify new genes with tumor-specific expression, we applied a cDNA subtraction approach, i.e., representational difference analysis, to a human sarcoma cell line. We obtained two cDNA clones that appeared to be tumor specific. The corresponding genes were named SAGE and HAGE because they have the same pattern of expression as genes of the MAGE family. SAGE encodes a putative protein of 904 amino acids and shows no homology to any recorded gene. Like the MAGE-A genes, it is located in the q28 region of chromosome X. Expression of gene SAGE was observed mainly in bladder carcinoma, lung carcinoma, and head and neck carcinoma but not in normal tissues, with the exception of testis. Gene HAGE, which is located on chromosome 6, encodes a putative protein of 648 amino acids. This protein is a new member of the DEAD-box family of ATP-dependent RNA helicases. Gene HAGE is expressed in many tumors of various histological types at a level that is 100-fold higher than the level observed in normal tissues except testis. Because of this tumor-specific expression, genes SAGE and HAGE ought to encode antigens that could be useful for antitumoral therapeutic vaccination.
Immunity
Several tumor antigens are recognized by autologous cytolytic T lymphocytes (CTL) on human melanoma MZ2-MEL. Some of them are encoded by genes MAGE.1 and MAGE.3, which are not expressed in normal tissues except in testis. Here, we report the identification of a new gene that codes for another of these antigens. This gene, named BAGE, codes for a putative protein of 43 aa and seems to belong to a family of several genes. The antigen recognized by the autologous CTL consists of BAGE-encoded peptide AARAVFLAL bound to an HLA-Cw*1601 molecule. Gene BAGE is expressed in 22% of melanomas, 30% of infiltrating bladder carcinomas, 1'0% of mammary carcinomas, 8% of head and neck squamous cell carcinomas, and 6% of non-small cell lung carcinomas. Like the MAGE genes, it is silent in normal tissues with the exception of testis. Because of its tumor-specific expression, the BAGE-encoded antigen may prove useful for cancer immunotherapy.