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T Boon

Publications and source records attributed to T Boon.

At least 91 records · Page 5Linked to original sources
PubMed1996

Infrequent expression of the MAGE gene family in uveal melanomas.

It has previously been reported that MAGE-1, -2, -3 and -4 genes are expressed in human cancers including cutaneous melanoma. MAGE-1 and MAGE-3 represent targets for specific immunotherapy because they encode peptide antigens which are recognised by cytotoxic T lymphocytes (CTL) when presented by HLA class I molecules, and pilot clinical trials with these peptides are currently in progress. It is likely that other members of the MAGE gene family may also encode antigens recognised by CTL. Uveal melanomas, like cutaneous melanomas, arise from melanocytes that are derived from the neural crest. To determine if uveal melanoma patients would be suitable for MAGE-peptide immunotherapy, the expression of MAGE-1, -2, -3 and -4 genes was assessed by reverse transcription followed by polymerase chain reaction (RT-PCR) amplification and ethidium bromide staining. Expression of MAGE genes was not detected in any of 27 primary tumours. Either MAGE-1 or MAGE-4 was expressed in only 2 of 26 metastatic samples, but expression of MAGE-2 or -3 was not detected. Our data suggest that, unlike cutaneous melanomas, uveal melanomas may not be suitable candidates for MAGE-peptide immunotherapy.

Antigens, Neoplasm↗
PubMed1996

A mutated HLA-A2 molecule recognized by autologous cytotoxic T lymphocytes on a human renal cell carcinoma.

Many human tumor cells have been shown to express antigens that are recognized by autologous cytotoxic T lymphocytes (CTL) and the molecular nature of a number of melanoma antigens has been defined recently. Here we describe the characterization of an antigen recognized on a renal cell carcinoma by autologous CTL clones. This antigen is encoded by the HLA-A2 gene present in the tumor cells. The sequence of this gene differs from the HLA-A2 sequence found in autologous peripheral blood lymphocytes by a point mutation that results in an arginine to isoleucine exchange at residue 170, which is located on the alpha-helix of the alpha 2 domain. Transfection experiments with the normal and mutated HLA-A2 cDNA demonstrated that this amino acid replacement was responsible for the recognition of the HLA-A2 molecule expressed on the tumor cells. The mutant HLA-A2 gene was also detected in the original tumor tissue from the patient, excluding the possibility that the mutation had appeared in vitro. Thus, HLA class I molecules carrying a tumor-specific mutation can be involved in the recognition of tumor cells by autologous CTL.

Aged↗
PubMed1996

Tumor rejection requires a CTLA4 ligand provided by the host or expressed on the tumor: superiority of B7-1 over B7-2 for active tumor immunization.

Although transfection to express any of a multitude of immunomodulatory molecules can lead to the rejection of murine tumors in vivo, it is not clear which of these cofactors are truly important for the induction of tumor-specific CTL. Examination of the costimuli used by the host immune response during the normal rejection of immunogenic tumors should reveal critical cofactors for CTL differentiation in vivo. The involvement of a host B7 family costimulator molecule in the rejection of immunogenic tum- variants of the mastocytoma P815 was explored. Rejection of immunogenic P815 variants was prevented by mCTLA4 gamma 3, a fusion protein between the extracellular domain of murine CTLA4 and the Fc portion of a murine IgG3 Ab, indicating the importance of a CTLA4 ligand provided by the host in the rejection of B7- tumors. Tumor rejection also was prevented by mCTLA4 gamma 3 in the absence of CD4+ cells, suggesting that CD8+ lymphocytes may receive direct costimulation by B7 in vivo. Finally, although living transfectants of poorly immunogenic P1.HTR cells expressing B7-1 or B7-2 were equally rejected by syngeneic mice, if delivered as multiple injections of irradiated cells, only B7-1 transfectants successfully induced CTL activity and protected against living tumor challenge. Our results indicate that a CTLA4 ligand is normally involved in the generation of CD8+ CTL against tumor Ag and suggest that immunization with irradiated B7-1-transfected tumor cells may be superior to immunization with irradiated B7-2 transfectants as an approach to tumor Ag vaccination in patients.

Abatacept↗
PubMed1996

A peptide recognized by human cytolytic T lymphocytes on HLA-A2 melanomas is encoded by an intron sequence of the N-acetylglucosaminyltransferase V gene.

A cytolytic T lymphocyte (CTL) clone that lyses many HLA-A2 melanomas was derived from a population of tumor-infiltrating lymphocytes of an HLA-A2 melanoma patient. The gene coding for the antigen recognized by this CTL was identified by transfection of a cDNA library. It is the gene which has been reported to code for N-acetylglucosaminyltransferase V (GnT-V). Remarkably, the antigenic peptide recognized by the CTL is encoded by a sequence located in an intron. In contrast to the fully spliced GnT-V mRNA, which was found in a wide range of normal and tumoral tissues, the mRNA containing the intron region coding for the antigen was not found at a significant level in normal tissues. This mRNA was observed to be present in about 50% of melanomas. Our results suggest that a promoter located near the end of the relevant intron is activated in melanoma cells, resulting in the production of an mRNA coding for the antigen.

Amino Acid Sequence↗
PubMed1996

An HLA-A2-restricted tyrosinase antigen on melanoma cells results from posttranslational modification and suggests a novel pathway for processing of membrane proteins.

T lymphocytes recognize antigens consisting of peptides presented by class I and II major histocompatibility complex (MHC) molecules. The peptides identified so far have been predictable from the amino acid sequences of proteins. We have identified the natural peptide target of a CTL clone that recognizes the tyrosinase gene product on melanoma cells. The peptide results from posttranslational conversion of asparagine to aspartic acid. This change is of central importance for peptide recognition by melanoma-specific T cells, but has no impact on peptide binding to the MHC molecule. This posttranslational modification has not been previously described for any MHC-associated peptide and represents the first demonstration of posttranslational modification of a naturally processed class I-associated peptide. This observation is relevant to the identification and prediction of potential peptide antigens. The most likely mechanism for production of this peptide leads to the suggestion that antigenic peptides can be derived from proteins that are translated into the endoplasmic reticulum.

Amino Acid Sequence↗
PubMed1996

Endogenous IL-12 is necessary for rejection of P815 tumor variants in vivo.

Although murine tumor cells have been transfected to express a multitude of different cytokines and shown to be rejected in vivo, it is unclear which of these factors might be useful to facilitate tumor Ag immunization schemes. A study of the normal immune mechanisms involved in tumor rejection when it naturally occurs should reveal critical signals for generation of antitumor CTL in vivo. The highly transfectable variant of P815, P1.HTR, was found to be rejected in the hind footpads by approximately one-third of syngeneic DBA/2 mice. Analysis of draining popliteal lymph nodes revealed a large influx of CD4+ and CD8+ T lymphocytes in all mice, indicating that a failure to reject was not due to the complete absence of an inflammatory response. However, although IL-2 and IL-3 were produced by lymph node cells from all mice, only approximately one-third generated a high IFN-gamma response. IL-4 was not detected. To explore a role for IL-12 in the induction of the IFN-gamma-producing phenotype, a histidine-tagged IL-12 fusion protein was expressed in mammalian cells and purified by nickel-chelate chromatography, and a rabbit antiserum was produced. Neutralization of IL-12 in vivo eliminated the high IFN-gamma response and prevented rejection of P1.HTR tumors and also of a more immunogenic tum- variant of P815, P198. Conversely, exogenous IL-12 delivered early during challenge with P1.HTR cells induced high IFN-gamma production and resulted in tumor rejection in most mice. Therefore, endogenous IL-12 is vital for the rejection of these tumors when it naturally occurs, supporting a role for exogenous administration of this cytokine to favor a Th1-like phenotype in the immunotherapy of cancer.

Animals↗
PubMed1996

A tyrosinase nonapeptide presented by HLA-B44 is recognized on a human melanoma by autologous cytolytic T lymphocytes.

The human tyrosinase gene has been reported previously to code for two distinct antigens recognized on HLA-A2 melanoma cells by autologous cytolytic T lymphocytes (CTL). By stimulating lymphocytes of melanoma patient MZ2 with a subclone of the tumor cell line of this patient, we obtained a CTL clone that lysed this subclone but did not lyse other subclones of the same melanoma cell line. The sensitive melanoma subclone was found to express a much higher level of tyrosinase than the others, suggesting that the antigen recognized by the CTL might be encoded by tyrosinase. Transfection of a tyrosinase cDNA demonstrated that the CTL clone indeed recognized a tyrosinase product presented by HLA-B*4403. The relevant antigenic peptide corresponds to residues 192-200 of the tyrosinase protein. Lymphoblastoid cells of the B*4402 subtype were not recognized by the CTL following incubation with the peptide. Nevertheless, by stimulating in vitro lymphocytes of a healthy HLA-B*4402 donor with autologous adherent cells pulsed with the same peptide, we obtained a CTL clone which recognized tumor cells expressing tyrosinase and HLA-B*4402. As HLA-B44 is expressed in 24% of Caucasians, the tyrosinase-B44 antigen may constitute a useful target for specific immunotherapy of melanoma.

Amino Acid Sequence↗
PubMed1996

A peptide encoded by the human MAGE3 gene and presented by HLA-B44 induces cytolytic T lymphocytes that recognize tumor cells expressing MAGE3.

The human MAGE3 gene is expressed in a significant proportion of tumors of various histological types, but is silent in normal adult tissues other than testis and placenta. Antigens encoded by MAGE3 may therefore be useful targets for specific antitumor immunization. Two antigenic peptides encoded by the MAGE3 gene have been reported previously. One is presented to cytolytic T lymphocytes (CTL) by HLA-A1, the other by HLA-A2 molecules. Here we show that MAGE3 also codes for a peptide that is presented to CTL by HLA-B44. MAGE3 peptides containing the HLA-B44 peptide binding motif were synthesized. Peptide MEVDPIGHLY, which showed the strongest binding to HLA-B44, was used to stimulate blood T lymphocytes from normal HLA-B44 donors. CTL clones were obtained that recognized not only HLA-B44 cells sensitized with the peptide, but also HLA-B44 tumor cell lines expressing MAGE3. The proportion of metastatic melanomas expressing the MAGE3/HLA-B44 antigen should amount to approximately 17% in the Caucasian population, since 24% of individuals carry the HLA-B44 allele and 76% of these tumors express MAGE3.

Amino Acid Sequence↗
PubMed1996

A new gene coding for an antigen recognized by autologous cytolytic T lymphocytes on a human renal carcinoma.

Previous reports have described antigens that are recognized on human melanoma cells by autologous cytolytic T lymphocytes (CTL). The genes coding for a number of these antigens have been identified. Here we report the cloning of a gene that codes for an antigen recognized by autologous CTL on a human renal carcinoma cell line. This antigen is presented by HLA-B7 and is encoded by a new gene that we have named RAGE1. No expression of RAGE1 was found in normal tissues other than retina. RAGE1 expression was found in only one of 57 renal cell carcinoma samples, and also in some sarcomas, infiltrating bladder carcinomas, and melanomas. This represents the first identification of an antigen recognized by autologous CTL on a renal tumor.

Amino Acid Sequence↗
PubMed1996

Recognition by human Vgamma9/Vdelta2 T cells of melanoma cells upon fusion with Daudi cells.

Daudi Burkitt's lymphoma cells, unlike other tumor cell lines, stimulate human T cells coexpressing the variable (V) region genes TCRG-V9 and V TCRD-V2 to proliferate and secrete lymphokines. Hybrids, derived by the fusion of Daudi cells with the human melanoma cell line MZ2-MEL 2.2, retain the morphology of melanoma cells. Unlike the parental melanoma cell line, these Daudi x MZ2-MEL 2.2 hybrids stimulate secretion of tumor necrosis factor (TNF) and granulocyte/macrophage colony stimulating factor (GM-CSF) by CD4-positive Vgamma9/Vdelta2 T-cell clones. Whereas the stimulator phenotype of Daudi cells behaves as a dominant trait in Daudi x melanoma hybrids, the expression of B-cell differentiation markers is suppressed. Thus, the gamma/delta T-cell ligand expressed by Daudi cells behaves as a dominant tumor antigen in Daudi x melanoma hybrids and is unrelated to the differentiated B-cell phenotype. Dominant expression of the Daudi ligand for human Vgamma9/Vdelta2 T cells in these hybrids may provide a basis for defining the stimulatory principle at the molecular level.

Burkitt Lymphoma↗
PubMed1996

The majority of autologous cytolytic T-lymphocyte clones derived from peripheral blood lymphocytes of a melanoma patient recognize an antigenic peptide derived from gene Pmel17/gp100.

Anti-melanoma cytolytic T-lymphocyte (CTL) clones were derived from peripheral blood lymphocytes of HLA-A2 melanoma patient LB265 after stimulation with the autologous tumor cell line LB265-MEL, which showed high expression of melanocyte-lineage specific genes. Of 55 CTL clones, 46 recognized HLA-A2-restricted antigens. These 46 CTL clones were studied for their ability to specifically release tumor necrosis factor in the presence of COS cells cotransfected with the HLA-A2 gene and the cDNA of either tyrosinase, Melan-A/MART1, Pmel17/gpl00, gp75/TRP1, or MSH receptor. Six CTL clones recognized the Melan-A/MART1 antigen, whereas the remaining 40 CTL clones recognized a Pmel17/gp100 antigen. These 40 anti-PmelI7/gpl00 CTL clones were all able to lyse T2 cells pulsed with the antigenic peptide YLEPGPVTA, as previously reported. The T-cell receptor beta chain hypervariable region was sequenced and found to be identical in the 15 CTL clones analyzed. Taken together, these data show a high frequency of Pmell7/gp100-specific T cells in autologous antitumor CTL clones derived from peripheral blood of a melanoma patient.

Amino Acid Sequence↗
PubMed1996

[Rejection antigens of tumors and specific immunotherapy of cancer].

Human tumors carry antigens that are recognized by the patients' cytolytic T lymphocytes. An important group of antigens is coded by the MAGE family of genes. These antigens are expressed in a significant proportion of tumors of numerous histological types but not in normal tissues. Clinical trials are underway in an attempt to immunize patients suffering from metastatic melanomas using peptides coded by the MAGE genes. Regressions have been observed in 5 of the 17 immunized patients.

Antigens, Neoplasm↗
PubMed1995

A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma.

Human melanoma MZ2-MEL expresses several distinct antigens that are recognized by autologous cytolytic T lymphocytes (CTL). Some of these antigens are encoded by genes MAGE-1, MAGE-3, and BAGE, which are expressed in a large fraction of tumors of various histological types but are silent in normal adult tissues with the exception of testis. We report here the identification of the gene coding for MZ2-F, another antigen recognized by autologous CTL on MZ2-MEL cells. This gene, which was named GAGE-1, is not related to any presently known gene. It belongs to a family of genes that are expressed in a variety of tumors but not in normal tissues, except for the testis. Antigenic peptide YRPRPRRY, which is encoded by GAGE-1, is recognized by anti-MZ2-F CTL on class I molecule HLA-Cw6. The two genes of the GAGE family that code for this peptide, namely GAGE-1 and GAGE-2, are expressed in a significant proportion of melanomas (24%), sarcomas (25%), non-small cell lung cancers (19%), head and neck tumors (19%), and bladder tumors (12%). About 50% of melanoma patients carry on their tumor at least one of the presently defined antigens encoded by the MAGE, BAGE, and GAGE genes.

Amino Acid Sequence↗
PubMed1995

A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma.

We have identified an antigen recognized on a human melanoma by autologous cytolytic T lymphocytes. It is encoded by a gene that is expressed in many normal tissues. Remarkably, the sequence coding for the antigenic peptide is located across an exon-intron junction. A point mutation is present in the intron that generates an amino acid change that is essential for the recognition of the peptide by the anti-tumor cytotoxic T lymphocytes. This observation suggests that the T-cell-mediated surveillance of the integrity of the genome may extend to some intronic regions.

Alleles↗
PubMed1995

Structure, chromosomal location, and expression pattern of three mouse genes homologous to the human MAGE genes.

The human MAGE1 gene directs the expression of an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. MAGE1 belongs to a family of genes that are expressed in a number of tumors of various histological types but not in normal tissues except testis. The MAGE genes are arranged in two groups that are located within two different regions of the human X chromosome (Xq26-qter and Xp21.3). By hybridizing mouse genomic libraries with a MAGE1 probe, we identified three homologous genes. Two of these mouse genes, Smage1 and Smage2, are more than 99% identical to each other and encode the same protein of 330 aa. The 5' noncoding region of Smage2 provides the potential for regulating the expression of the gene through several different promoters located in front of alternative first exons. The third gene, Smage3, has the structure of a processed transcript. It codes for a protein with only 11 aa substitutions with respect to the Smage1/2 product. Somatic cell hybrids and interspecific backcross analysis showed that Smage3 is autosomal and that Smage1 and Smage2 are located between the Dmd and the Ar loci on the mouse X chromosome. Since this region is syntenic to the human Xp21.1-p22.1 region, we conclude that Smage1 and Smage2 are homologous to the MAGE-Xp rather than to the MAGE-Xq genes. Smage1/2 transcripts were detected in several tumor and embryonal cell lines but not in normal mouse tissues with the exception of testis. Expression of Smage3 was found in embryos from Day 11 to Day 15.

Amino Acid Sequence↗