Biomedical subjects

S Shichijo

Publications and source records attributed to S Shichijo.

At least 37 records · Page 2Linked to original sources

PubMed2000

Expression of the SART1 tumor-rejection antigens in colorectal cancers.

PURPOSE: Colorectal cancer is one of the major causes of cancer death in the world, including in the United States and Japan. We recently identified the tumor-rejection antigen gene SART1, which encodes both the SART1(259) antigen expressed in the cytosol of epithelial cancers and the SART1(800) antigen expressed in the nucleus of the majority of proliferating cells. This study investigated the expression of these tumor antigens to explore a potential molecule for specific immunotherapy of colorectal cancer patients. METHODS: SART1 antigens were investigated by Western blotting in six colorectal cancer cell lines and in 33 colorectal cancer tissues. The cancer cell lines were tested for their ability to stimulate interferon-gamma production by the human-leukocyte-antigen-A24-restricted and SART1-specific cytotoxic T lymphocytes and were also tested for their susceptibility to the lysis by the cytotoxic T lymphocytes. RESULTS: The SART1(259) antigen was detected in the cytosol of four of six cancer cell lines, 13 of 33 (39 percent) cancer tissues, and 0 of 20 nontumorous colorectal tissues. The SART1(800) antigen was expressed in the nucleus of all the colorectal cancer cell lines, 18 of 33 (55 percent) cancer tissues, and 0 of 20 nontumorous tissues. The human-lymphocyte-antigen-A24-restricted and SART1-specific cytotoxic T lymphocytes killed the human-lymphocyte-antigen-A24+ SART1(259+) cancer cells. CONCLUSIONS: The SART1(259) antigen could be an appropriate target molecule for specific immunotherapy of approximately 40 percent of the human-lymphocyte-antigen-A24+ patients with colorectal cancer.

Adenocarcinoma↗

PubMed2000

Expression of tumor-rejection antigens in gynecologic cancers.

We recently reported the four tumor-rejection antigens (SART1(259), SART2, SART3, and ART4) that possess tumor epitopes capable of inducing HLA-A2402-restricted cytotoxic T lymphocytes (CTLs) in cancer patients. This study investigated the expression of these tumor antigens in gynecologic cancers, including 33 ovarian cancers, 38 cervical cancers, and 40 endometrial cancers. SART1(259) antigen was detected in 56%, 35%, and 30% of ovarian, cervical and endometrial cancers, while SART2 antigen was detected in 46%, 66%, and 30% of these cancers, respectively. Both SART3 and ART4 antigens were detectable in the majority of these gynecologic cancers tested. In contrast, none of these antigens was detectable in any of the normal ovarian and uterine tissues tested. Peripheral blood mononuclear cells (PBMCs) of HLA-A24(+) patients with gynecologic cancers were found to produce significant levels of interferon-gamma in response to HLA-A24(+) SART3(+) gynecologic cancer cells after having been stimulated three times in vitro with either SART3(109 - 118) or SART3(315 - 323) peptide. These PBMCs lysed HLA-A24(+) SART3(+) gynecologic cancer cells, but not HLA-A24(-) SART3(+) gynecologic cancer cells or HLA-A24(+) normal cells. Therefore, these four antigens and their peptides, including SART3 peptides, would be appropriate molecules for use in specific immunotherapy of HLA-A24(+) gynecologic cancer patients.

Antigens, Neoplasm↗

PubMed2000

[Human tumor-rejection antigens and peptides from genes to clinical research].

One of the most significant advances in the field of modern tumor immunology is the identification of genes encoding tumor-rejection antigens that are recognized by human leukocyte antigen (HLA) class I-restricted and tumor-specific cytotoxic T lymphocytes (CTLs). Several peptides encoded by these genes are now under clinical trial as cancer vaccines, and major tumor regression has been observed in some melanoma patients. These results indicate that identification of the peptides capable of inducing CTLs may provide a new modality of cancer therapy. We investigated tumor-rejection antigens from epithelial cancers, and reported 7 genes encoding tumor-rejection antigens and peptides available for specific immunotherapy of HLA-A26 or -A24 patients with epithelial cancers. Furthermore, we identified more than 10 genes encoding tumor-rejection antigens and peptides available for specific immunotherapy of HLA-A2 patients with epithelial cancers. Therefore these new antigens and peptides could be applicable to the treatment of numerous epithelial cancer patients worldwide. Phase I clinical trials of cancer vaccine with these peptides for epithelial cancer patients are in progress at our university. Basic and clinical research will provide new insights for a better understanding of the molecular basis of T cell-mediated recognition of cancer cells and be important for the development of cancer vaccines.

Antigens, Neoplasm↗

PubMed1999

Expression of the tumor-rejection antigen SART1 in brain tumors.

We have reported a tumor-rejection antigen, SART1(259), possessing tumor epitopes capable of inducing cytotoxic T lymphocytes (CTLs) in epithelial-cancer patients. This study investigated the expression of SART1(259) antigen in brain tumors, to explore for a potential molecule for use in specific immunotherapy of patients with brain tumors. The SART1(259) antigen was detected in the cytosol fraction of 13 of 18 (72%) glioma cell lines and in 12 of 34 (35%) brain-tumor tissues, with a higher rate of expression among malignant gliomas (5/10, 50%) and schwannomas (3/4). HLA-A24-restricted and SART1-specific CTLs recognized the HLA-A24+ and SART1(259)+ glioma cells, and the levels of recognition correlated both with HLA-A24-antigen expression level and with the concentration of the SART1 peptide antigen. Therefore, the SART1(259) antigen could be a target molecule for specific immunotherapy of patients with brain tumors expressing HLA-class-1 antigens.

Antigens, Neoplasm↗

PubMed1999

Identification of a gene coding for a protein possessing shared tumor epitopes capable of inducing HLA-A24-restricted cytotoxic T lymphocytes in cancer patients.

Genes encoding tumor epitopes that are capable of inducing CTLs against adenocarcinomas and squamous cell carcinomas, two major human cancers histologically observed in various organs, have rarely been identified. Here, we report a new gene from cDNA of esophageal cancer cells that encodes a shared tumor antigen recognized by HLA-A2402-restricted and tumor-specific CTLs. The sequence of this gene is almost identical to that of the KIAA0156 gene, which has been registered in GenBank with an unknown function. This gene encodes a Mr 140,000 protein that is expressed in the nucleus of all of the malignant tumor cell lines tested and the majority of cancer tissues with various histologies, including squamous cell carcinomas, adenocarcinomas, melanomas, and leukemia cells. However, this protein was undetectable in the nucleus of any cell lines of nonmalignant cells or normal tissues, except for the testis. Furthermore, this protein was expressed in the cytosol of all of the proliferating cells, including normal cells and malignant cells, but not in normal tissues, except for the testis and fetal liver. Two peptides of this protein were recognized by HLA-A2402-restricted CTLs and were able to induce HLA-A24-restricted and tumor-specific CTLs from peripheral blood mononuclear cells of most of HLA-A24+ cancer patients tested, but not from peripheral blood mononuclear cells of any healthy donors. These peptides may be useful in specific immunotherapy for HLA-A24+ cancer patients with various histological types.

Antigens, Neoplasm↗

PubMed1999

Identification of a SART-1-derived peptide capable of inducing HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes.

We have described the SART-1 gene-encoding peptides recognized by HLA-A2601-restricted and tumor-specific cytotoxic T lymphocytes (CTLs). We now have investigated whether SART-1 encodes peptides capable of inducing the HLA-A24-restricted CTLs. Among the 18 different peptides with HLA-A24-binding motifs, the SART-1(690-698) peptide (EYRGFTQDF) was most strongly recognized by the HLA-A24-restricted and tumor-specific CTLs established from an esophageal cancer patient. After a third stimulation in vitro, this peptide induced HLA-A24-restricted CTLs recognizing the SART-1(259)+ tumor cells in PBMCs of all HLA-A24 homozygous and the majority of HLA-A24 heterozygous cancer patients and healthy donors tested. A similar activity, induction of CTLs from PBMCs, was observed in the Saccharomyces cerevisiae-derived nonapeptide (EYRGFTPMF) that shares 7 amino acids with the SART-1(690-698) peptide. The SART-1(690-698) peptide-induced CTL activity was significantly higher in PBMCs of HLA-A24 homozygotes than in HLA-A24 heterozygotes. The CTL precursor frequency in PBMCs after a third stimulation in vitro with the SART-1(690-698) peptide was high (>1/200) in both cancer patients and healthy donors. The SART-1(690-698) peptide could thus be useful for specific immunotherapy of HLA-A24+ cancer patients.

Antigens, Neoplasm↗

PubMed1999

Expression of the SART-1 tumor rejection antigen in breast cancer.

We investigated in breast cancers the expression of the SART-1 gene encoding tumor rejection antigens. SART-1 mRNA was expressed in all of the samples tested. The SART-1(800) antigen was detectable in 20 of 50 (40%) breast cancer tissues and all breast cancer cell lines tested, but not in normal breast tissues. The SART-1(800)+ breast cancer cells transfected with HLA-A2601 or HLA-A2402 cDNA were recognized by the HLA-A26-restricted and SART-1-specific cytotoxic T lymphocytes (CTLs) or the HLA-A24-restricted and SART-1-specific CTLs, respectively. Among the 20 SART-1(800)+ tumors, 9 or 8 tumors expressed estrogen receptor or progesterone receptor, respectively. Therefore, the patients with HLA-A26 or -A24 haplotype might be appropriate candidates for specific immunotherapy with the SART-1 peptides independently or in combination with hormone therapy.

Antigens, Neoplasm↗

PubMed1998

A gene encoding antigenic peptides of human squamous cell carcinoma recognized by cytotoxic T lymphocytes.

Except for melanomas, tumor antigens recognized by cytotoxic T lymphocytes (CTLs) are yet unidentified. We have identified a gene encoding antigenic peptides of human squamous cell carcinomas (SCCs) recognized by human histocompatibility leukocyte antigens (HLA)- A2601-restricted CTLs. This gene showed no similarity to known sequences, and encoded two (125- and 43-kilodalton [kD]) proteins. The 125-kD protein with the leucine zipper motif was expressed in the nucleus of the majority of proliferating cells tested, including normal and malignant cells. The 43-kD protein was expressed in the cytosol of most SCCs from various organs and half of lung adenocarcinomas, but was not expressed in other cancers nor in a panel of normal tissues. The three nonapeptides shared by the two proteins were recognized by the KE4 CTLs, and one of the peptides induced in vitro from peripheral blood mononuclear cells (PBMCs) the CTLs restricted to the autologous tumor cells. The 43-kD protein and this nonapeptide (KGSGKMKTE) may be useful for the specific immunotherapy of HLA-A2601(+) epithelial cancer patients.

Amino Acid Sequence↗

PubMed1998

Expression of the SART-1 antigens in uterine cancers.

We recently reported that the SART-1 gene, encoding the SART-1(259) tumor antigen which is recognized by HLA-A26-restricted cytotoxic T lymphocytes (CTLs), is expressed in the cytosol of squamous cell carcinomas and adenocarcinomas. The present study deals with the expression of SART-1(259) and SART-1(800) antigens in uterine cancers. The SART-1(259) antigen was detected in the cytosol fraction of 4 of 8 uterine cancer cell lines, 24 of 74 (32%) uterine cancer tissues, 0 of 7 uterine myomas, and 0 of 5 non-tumorous uterine tissues. The SART-1(800) antigen was expressed in the nuclear fraction of all the uterine cancer cell lines, 41 of 74 (55%) uterine cancer tissues, 0 of 7 myomas, and 3 of 5 non-tumorous uterine tissues. The SART-1(259)+ uterine cancer cells were recognized by HLA-A24 restricted and SART-1 specific CTLs. Therefore, SART-1(259) antigen could be an appropriate vaccine candidate for a relatively large number of uterine cancer patients.

Adenocarcinoma↗

PubMed1998

Sequence analysis of genes encoding rodent homologues of the human tumor-rejection antigen SART-1.

Human SART-1 (hSART-1) gene encodes a 125 kD protein with a leucine-zipper motif expressed in the nucleus of all proliferating cells, and a 43 kD protein expressed in the cytosol of most epithelial cancers. In this study, two rodent genes (rSART-1 and mSART-1) homologous to hSART-1 were cloned from cDNA libraries of murine brain and a rat tumor cell line, respectively. mSART-1 and rSART-1 were highly homologous to hSART-1 with 86% and 84% identity at the nucleotide level, and 95% and 91% at the protein level, respectively. The leucine zipper domain and two basic amino acid portions that bind DNA, as well as peptide sequences recognized by human cytotoxic T lymphocytes (CTLs), were all conserved in these rodent genes. Nuclear protein homologous to the 125 kD hSART-1(800) protein, but not to the 43 kD cytosol SART-1(259) protein, was detectable with specific antibody in the nuclear fractions of rodent tumor cell lines, and normal rodent fetal liver and testis. These rodent genes should be a novel tool for studies on the biological roles of the SART-1 gene, and also in the construction of animal models of specific immunotherapy using SART-1 gene products.

Amino Acid Sequence↗

PubMed1997

Detection of MAGE-4 protein in sera of patients with head-and-neck squamous-cell carcinoma.

The MAGE-4 gene, a member of the MAGE gene family, is expressed in various cancers, including head-and-neck squamous-cell carcinomas (HN-SCC), but is not expressed in any normal tissues except for the testis and placenta. The aim of this study was to determine whether serum MAGE-4 protein is a useful tumor marker for detection of HN-SCC. An enzyme-linked immunosorbent assay was used to measure serum level of MAGE-4 protein. The serum level of MAGE-4 in pre-operative HN-SCC patients was significantly higher than that in patients with non-malignant diseases (NMD) of the head and neck, volunteers undergoing cancer screening (VOL), or healthy donors (HD). When the cut-off level was determined at 1.15 ng/ml (mean plus 3 SD of HD), sera from 28 of 96 patients with HN-SCC (p < 0.0001 vs. the other groups), 7 of 82 patients with NMD, 2 of 92 with VOL, and 0 of 68 HD were positive for MAGE-4. Serum levels of MAGE-4 protein in all 7 HN-SCC patients whose sera were positive for MAGE-4 before operation decreased after operation, and, in one patient, a renewed rise in serum level was followed by recurrence. These results indicate that MAGE-4 protein is detectable in sera of a significant number of HN-SCC patients, and that serum MAGE-4 protein might be a useful tumor marker to monitor the recurrence of MAGE-4-positive HN-SCC.

Adult↗

PubMed1997

Detection of MAGE-4 protein in sera of lung cancer patients.

We investigated the level of MAGE-4 protein in sera of patients with primary lung cancer to understand better the biological roles of the MAGE proteins. MAGE-4 protein was detected as a non-degraded form in both the supernatant of a MAGE-4+ tumor cell line and in a patient's serum. Serum level of the MAGE-4 protein in lung cancer patients (n=100, mean=1.17 ng/ml) was significantly higher than that in either patients with benign pulmonary diseases (n=80, 0.33 ng/ml) or healthy donors (n=68, 0.32 ng/ml). It was higher than the cutoff level (1.15 ng/ml) in 34 of 100 cancer patients, but not in anyone in the other groups.

Adult↗

PubMed1997

Detection of MAGE-4 protein in the sera of patients with hepatitis-C virus-associated hepatocellular carcinoma and liver cirrhosis.

The aim of this study was to determine whether MAGE-4 protein is detectable in sera of patients with hepatocellular carcinoma and other liver diseases. An enzyme-linked immunosorbent assay was employed for detection of MAGE-4 protein in sera of liver disease patients, healthy men and women (control I) and those undergoing prostatic cancer screening (control II). MAGE-4 protein levels in sera of patients with hepatitis C virus-associated HCC (HCC-C) (n = 45, mean = 2.160 ng/ml) and HCV-associated cirrhosis (LC-C) (n = 55, 1.072 ng/ml) were significantly higher (P < 0.0001) than those of control I (0.327 ng/ml) or control II (0.394 ng/ml). MAGE-4 protein was positive in 21/45 (46.7%) HCC-C patients and 18/55 (32.7%) LC-C patients (cut-off, mean plus 2 SD in healthy controls) but in 0/12 (0%) hepatitis B virus-associated HCC (HCC-B) patients, 3/49 (6.1%) hepatitis B virus-associated LC (LC-B) patients, 4/47 (8.5%) alcoholic liver disease patients, and 1/49 (2.0%) controls. Serum MAGE-4 protein level may be useful as a marker for identification of LC-C patients suffering from HCC that is undetectable by presently available methods.

Adult↗

PubMed1997

Development of cancer vaccine by tumor rejection antigens.

Identification of the MAGE genes allowed us the molecular approach to identify genes encoding tumor rejection antigens expressed on human cancer cells. MAGE-1 proteins are normal tissue antigens compartmentalized in the particular testicular cells playing an important role in the early phase of the spermatogenesis. The MAGE-1, -2, -3, -4 and -6 genes are preferentially expressed in many different cancers at both the mRNA and protein levels. The MAGE genes, particularly MAGE-1, became positive in relatively advanced stages of cancers and recurrent cancers. Approximately one-third to half of human cancers except for myelo-monocytic leukemia expressed at least one of these MAGE genes. The MAGE gene products shall be appropriate target molecules for development of new cancer vaccine.

Animals↗

PubMed1996

A monoclonal antibody KIS-1 recognizing a new membrane antigen on human squamous-cell carcinoma.

A KIS-1 monoclonal antibody (MAb) (IgG1, kappa) recognizing a membrane antigen on human squamous-cell carcinomas (SCC) was developed to understand their antigenicity using an esophageal SCC as an immunogen. The KIS-1 MAb recognized a membrane antigen on a majority of esophageal, lung, and oral- cavity SCC by immunofluorescent and by immunohistochemical analyses. In contrast, it showed little reactivity to adenocarcinomas from different organs, and none to keratinocyte cell lines. This MAb showed reactivity to the cells in the basal layer of normal esophageal epithelium adjacent to the esophageal SCC, but none of the other normal tissues, including esophageal epithelium far from the SCC and that from patients with non-malignant disease. The KIS-1 MAb immunoprecipitated a 46-kDa membrane protein of the esophageal SCC in non-reducing and in reducing conditions. It recognized the 46- and the 40-kDa proteins of the esophageal SCC by immunoblot analysis. These results suggest that the KIS-1 MAb recognizes a new membrane antigen preferentially expressed on SCC, and that this antigenicity is shared only by the cells in the basal layer of the esophageal epithelium adjacent to SCC. The KIS-1 MAb may be a new tool for understanding the antigenicity of SCC.

Animals↗

PubMed1996

Melanocyte lysis by cytotoxic T lymphocytes recognizing the MART-1 melanoma antigen in HLA-A2 patients with Vogt-Koyanagi-Harada disease.

The MART-1/Melan-A melanoma antigen recognized by the majority of HLA-A2-restricted tumor-infiltrating lymphocytes is a self antigen expressed on melanocytes and the retina. We have investigated whether Vogt-Koyanagi-Harada (VKH) disease and sympathetic ophthalmia (SO), systemic inflammatory disorders affecting various organs containing melanocytes, are autoimmune diseases directed toward the MART-1 antigen. In two of three patients with VKH disease and one patient with SO, CD8(+) T cell clones (TCC) form intraocular fluid of HLA-A2(+) patients lysed T2 cells when pulsed with a HLA-A2-binding MART-1 peptide, but not a HLA-A2-binding pMel-17 or tyrosinase peptide, in a HLA-A2-restricted manner. In addition, Th, TCC recognizing a HLA-A2-binding MART-1 peptide were also established from peripheral blood mononuclear cells of a patient with VKH disease. In contrast, either CD4(+) TCC from these patients or CD8(+) TCC from the intraocular fluid of HLA-A2(+) patients with uveitis associated with Behcet's disease or HTLV-1 uveitis did not show this cytotoxicity. The results demonstrate that the MART-1 peptide-specific cytotoxic T lymphocytes lyse melanocytes in the eye of patients with VKH disease or SO, suggesting that these diseases are autoimmune diseases directed toward the MART-1 antigen in HLA-A2(+) patients.

Antigens, Neoplasm↗

PubMed1996

Human tumor rejection antigens MAGE.

Characterization of the MAGE genes has facilitated a molecular approach to identification of the genes encoding tumor-rejection antigens expressed on human cancer cells. MAGE proteins are normal tissue antigens compartmentalized in testicular cells that play an important role in the early phase of spermatogenesis. MAGE-1, -2, -3, -4, and -6 genes are preferentially expressed in many different cancers at both the mRNA and protein levels. More than half of human cancers of various histologic type express at least one of these MAGE genes. Demethylation induces MAGE antigens in cells, suggesting that MAGE genes are important developmentally regulated genes under methylating control. Thus, genetic instability in cells causing loss of this methylating control could result in the preferential expression of MAGE genes in cancer cells. Therefore, MAGE gene products may be appropriate target molecules for development of new cancer vaccine.

Amino Acid Sequence↗

PubMed1996

Induction of MAGE genes in lymphoid cells by the demethylating agent 5-aza-2'-deoxycytidine.

MAGE genes encoding tumor antigens recognized by cytotoxic T lymphocytes are appropriate target molecules for specific immunotherapy of cancer. We have investigated whether the demethylating agent 5-aza-2'-deoxycytidine (DAC) induces MAGE-1, -2, -3, and -6 in normal and malignant lymphoid cells. DAC induced these MAGE genes in both PHA/interleukin-2 (IL-2)-activated T cells from healthy donors and MAGE-negative T and B cell leukemias in most cases. It also induced MAGE-1 in IL-2-dependent T cell clones and all MAGE genes tested in Epstein-Barr virus-transformed B cell lines. Expression of MAGE-1 protein in the cells was confirmed by western blot analysis with anti-MAGE-1 polyclonal antibody. Therefore, demethylation is a potent stimulus to induce MAGE genes in both normal and malignant lymphoid cells.

Amino Acid Sequence↗