Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We identified a novel 8.1-kb human melanoma gene, MG50, derived from subtractive hybridization with a squamous lung carcinoma cell line, LU-1. 6.8 kb containing an open reading frame were sequenced, and the structure of the encoded 1496 amino acid protein was deduced. With HLA-A2.1-transduced Drosophila cells as antigen-presenting cells, we identified six epitopes restricted by HLA-A2.1 that elicited CTLs in vitro. Reactivity of the CTLs to melanoma cells containing MG50 indicated that the epitopes were displayed naturally. Significant cross-reactivity of CTLs immunized against a melanoma cell line that lacked HLA-A2.1 indicated that at least four of the epitopes were also recognized in a different HLA class I context, most likely HLA-A*6802. By quantitative reverse transcription, MG50 message was found in one of two skin melanoma cell lines, an ocular melanoma cell line, two of four metastatic skin melanomas, two of three mammary carcinomas, one of two colon carcinomas, and an ovarian carcinoma. Of six normal tissues, MG50 was found only in a specimen of normal skin and was absent from a congenital nevus. It is likely that MG50 is the gene for the interleukin 1 receptor antagonist because a reported sequence of cDNA from the latter had a sequence of 528 bases in the 3' region, a long contiguous base sequence, and 176 encoded amino acids identical with those of MG50. MG50 is one of the few melanoma-associated antigens that is not a differentiation antigen or a mutated protein. Because of its nature, it may prove to be important in the pathogenesis of the tumors in which it is found, as well as an immunogen and target for immunotherapy.
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PMID:A novel melanoma gene (MG50) encoding the interleukin 1 receptor antagonist and six epitopes recognized by human cytolytic T lymphocytes. 1110 12

In order to clarify the anti-tumor activity of IFN-gamma, we investigated the direct IFNluence of IFN-gamma on both the growth and cell-surface antigen expression of tumor cells. In the present study, four human lung cancer cell lines were used; two squamous cell lines (QG-56, QG-95) and two adenocarcinoma cell lines (PC-9, PC-12). In all four tumor cell lines, mutations were detected in exon 7 of the p53 gene by a PCR-FSSCP analysis. The proliferation of QG-56 or QG-95 was inhibited by IFN-gamma in a dose-dependent manner with about 70% inhibition at 1000 JRU/ml while that of PC-9 was slightly inhibited with maximally 25% inhibition at 1000 JRU/ml. The growth of PC-12 was not inhibited at all. In QG-56, QG-95 and PC-9, the fraction of cells in G1 phase increased while the fractions of cells in both S and G2/M phases decreased after exposure to IFN-gamma (200 JRU/ml) for 72 h. The growth inhibition by long-term exposure to IFN-gamma was irreversible in QG-56. After culture in the presence of IFN-gamma (200 JRU/ml) for 14-16 days, tumor cells were examined for expression of various antigens, including HLA-class I, HLA-class II, and CEA. In all cell lines but PC-12, 100% of cells expressed HLA-class I after incubation with IFN-gamma. Both HLA-class II and CEA were also induced in those cell lines. The proportion of HLA-class II-positive cells or that of CEA-positive cells varied among the cell lines. Of the three antigens, the degree of HLA-class II expression paralleled that of growth inhibition by IFN-gamma treatment. These results suggested that in various function of IFN-gamma against tumor cells, the anti-proliferative effect might be closely linked with the induction of HLA-class II probably through a similar posttranscriptional process, independent of the function of p53 gene.
Lung Cancer 2000 Dec
PMID:Direct IFNluence of interferon-gamma on proliferation and cell-surface antigen expression of non-small cell lung cancer cells. 1113 1

HLA-class I-specific natural killer cell receptors (HNKR) have been described to significantly interfere with both specific and non-specific functional activities of T lymphocytes. Despite the clear evidences obtained in T cells derived from peripheral blood, little is known about the activity of HNKR expressed in tumor infiltrating lymphocytes. For this reason, we have studied T lymphocytes derived from advanced non small cell lung cancers (NSCLC). The population of T cells expressing the HNKR(+) phenotype was rare both in NSCLC-associated lymphocytes and in the peripheral blood. The two populations were clearly oligoclonal, as shown by the analysis of T cell receptor repertoire. Interestingly, while HNKR(+) T cells derived from the peripheral blood belonged to the CD45R0 phenotype, the large majority of HNKR(+) T cells in TIL were CD45RA. Functionally, all HNKR(+) T cells displayed a cytolytic activity against allogeneic NSCLC. Autologous NSCLC, tested in a single patient, was lysed efficiently by HNKR(+) T cells, thus suggesting that at least in this model, the presence of HNKR did not significantly interfere with the functional capacity of effector cells.
Lung Cancer 2001 Dec
PMID:Analysis of HLA-class-I specific natural killer cell receptors expressed on T lymphocytes infiltrating non-small-cell lung cancer. 1171 37

Epithelial cell adhesion molecule (Ep-CAM) derived antigenic peptides have been identified that can be recognized by cytotoxic T lymphocytes (CTL) in a major histocompatibility complex (MHC) class I restricted fashion. Thus, altered expression of Ep-CAM in a variety of human tumors might render a potential target for T cell mediated therapy. We have examined, whether the novel HLA-A*0201 restricted peptide ILYENNVIT (184-192) corresponding to Ep-CAM and one heteroclitic modified variant peptide previously demonstrated to be immunogenic in the human system can elicit antigen specific CTL responses in HLA-A2 positive patients with history of Ep-CAM expressing cancer of lung and colon. Specific CTL recognition of T2 target cells pulsed with the native peptide as well as of the lung cancer cell line A549 indicates that an appropriate T cell repertoire can be expanded from peripheral blood from patients in clinical remission and with advanced cancer. Despite an overall low frequency, peptide specific precursor CTLs could be readily expanded from peripheral blood from 6/8 patients that were diagnosed previously with Ep-CAM expressing lung cancer and 4/8 control individuals (2/5 healthy donors and 2/3 colon cancer patients). CTLs from three of five lung cancer patients tested also lyzed the HLA-A2(+) and Ep-CAM expressing lung cancer cell line A549. We did not detect an increased frequency of pCTLs after peripheral blood monocytes (PBMCs) were stimulated with the heteroclitic compound peptide. The results of our study indicate that Ep-CAM specific precursor CTL can be expanded in vitro and a specific T cell response against this epitope can be elicited in patients at various stages of lung cancer.
Lung Cancer 2002 May
PMID:Functional detection of epithelial cell adhesion molecule specific cytotoxic T lymphocytes in patients with lung cancer, colorectal cancer and in healthy donors. 1195 49

Half of all patients with limbic encephalitis and small cell lung carcinoma (SCLC) have anti-Hu antibodies that react with all of central and peripheral nervous system neuronal nuclei in immunohistochemical studies and 35- to 40-kDa reactive bands on western blots of extracts from isolated central nervous system neurons. The roles of anti-Hu antibodies in neuronal damage, however, have yet to be shown. Evidence of infiltration of CD8-positive T cells to tumors and affected nervous tissues and limited use of the T cell receptor repertoire in the central nervous system suggests that CD8-positive cytotoxic T cells (CTL) cause neuronal loss. We found the HLA B7 supertype in all of seven Japanese patients with anti-Hu syndrome. We identified HLA class I-restricted, CD 8-positive cytotoxic T cell activity in peripheral blood from three patients with anti-Hu syndrome for five peptides with binding motifs for the HLA B7 supertype in the amino acid sequence of the Hu protein. This study support the involvement of CD8-positive cytotoxic T cells in the development of paraneoplastic neurological syndrome with anti-Hu antibodies.
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PMID:Cytotoxic T cell activity against peptides of Hu protein in anti-Hu syndrome. 1216 87

Large tumor burdens in advanced non-small-cell lung carcinoma (NSCLC) are thought to be immunosuppressive. To determine whether CD8-mediated immune responses could be elicited in stage IIIB/IV NSCLC patients, 14 subjects were immunized several times with allogeneic NSCLC cells transfected with CD80 (B7.1) and HLA-A1 or A2. Patients enrolled were matched or unmatched at the HLA A1 or A2 locus and their immune response compared. Immunization significantly increased the frequencies of interferon-gamma secreting CD8 T cells in all but one patient in response to ex vivo challenge with NSCLC cells. The CD8 response of matched and unmatched patients was not statistically different. NSCLC reactive CD8 cells did not react to K562. Clinically, five of 14 patients responded to immunization with stable disease or partial tumor regression. The study demonstrates that CD8 Ifn-gamma responses against nonimmunogenic or immunosuppressive tumors can be evoked by cellular vaccines even at advanced stages of disease. The positive clinical outcome suggests that nonimmunogenic tumors may be highly susceptible to immune effector cells generated by immunization.
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PMID:Induction of CD8 T-cell-Ifn-gamma response and positive clinical outcome after immunization with gene-modified allogeneic tumor cells in advanced non-small-cell lung carcinoma. 1460 71

A wide variety of human carcinomas have low expression of tumor-associated antigen presentation in the context of MHC class I antigens due to defects in the antigen presentation pathway. This immune evasion mechanism renders many tumors unrecognizable by host immune surveillance mechanisms. The present study examines the expression of HLA, tapasin, transporter associated with antigen processing 1 (TAP1), and beta2 microglobulin in human small cell lung carcinoma and non-small cell lung carcinoma. Immunohistochemical staining showed severe impairment of the antigen presentation pathway in all patients. In order to recover tumor immunogenicity, a nonreplicating adenovirus expressing human TAP1 (AdhTAP1) was used to restore the expression of TAP1 in the antigen presentation pathway-deficient mouse lung carcinoma cell line, CMT.64. Infection of CMT.64 cells with AdhTAP1 increased MHC class I antigen surface expression, antigen presentation, and susceptibility to antigen-specific CTLs. Fluorescence-activated cell sorting and ELISPOT analysis showed that AdhTAP1 treatment significantly increased dendritic cell cross-presentation and cross-priming of tumor antigens. Furthermore, ex vivo and in vivo AdhTAP1 treatment significantly retarded tumor growth and increased survival of mice bearing CMT.64 tumors. Fluorescence-activated cell sorting analysis and immunohistochemical staining showed a significant increase in CD8+ and CD4+ T cells and CD11c+ dendritic cells infiltrating the tumors. The results show that TAP should be considered as a part of the immunotherapies for various cancers because it is likely to provide a general method for increasing immune responses against tumors regardless of the antigenic composition of the tumor or the MHC haplotypes of the host.
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PMID:Restoration of the expression of transporters associated with antigen processing in lung carcinoma increases tumor-specific immune responses and survival. 1614 Sep 64

Conventional treatment of recurrent and metastasized prostate cancer (CaP) remains inadequate; this fact mandates development of alternative therapeutic modalities, such as specific active or passive immunotherapy. Previously, we reported the identification of a novel highly immunogenic HLA-A*0201-restricted Prostatic Acid Phosphatase-derived peptide (PAP-3) by a two-step in vivo screening in an HLA-transgenic (HHD) mouse system. In the present study we aimed at elucidating the efficiency of PAP-3-based vaccine upon active antitumor immunization. To this end we established preventive and therapeutic carcinoma models in HHD mice. The 3LL murine Lewis lung carcinoma clone D122 transduced to express HLA-A*0201 and PAP served as a platform for these models. The HLA-A*0201-PAP-3 complex specific recombinant single chain scFV-PAP-3 antibodies were generated and used to confirm an endogenous PAP processing resulting in PAP-3 presentation by HLA-A*0201. PAP-3 based vaccines significantly decreased tumor incidence in a preventive immunization setting. Therapeutic vaccination of HHD mice with PAP-3 led to rejection of early established tumors and to increase of mouse survival. These results strongly support a therapeutic relevance of the identified CTL epitope upon active antitumor immunization. The newly established carcinoma model presented herein might be a useful tool for cancer vaccine design and optimization.
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PMID:Preventive and therapeutic vaccination with PAP-3, a novel human prostate cancer peptide, inhibits carcinoma development in HLA transgenic mice. 1673 49

Infiltration of CD3(+)CD8(+) cytotoxic T cells was analyzed by multiparameter confocal laser microscopy in a panel of 16 randomly selected stage I nonsmall cell lung carcinomas. T-cell infiltration was observed in the stroma (range 57-2,093 T cells/mm(2)) but also in the tumor epithelium (range 21-892 T cells/mm(2)) and showed wide variation between individual tumors. Interestingly, a significantly higher percentage of CD3(+)CD8(+) T cells was detected in the tumor epithelium compared to the stroma illustrating that cytotoxic T cells may preferentially migrate into tumor epithelium. Aberrant HLA class I antigen expression was observed in 69% of the nonsmall-cell lung carcinoma (NSCLC) tumors. One tumor of a squamous cell lung carcinoma patient with the highest number of tumor infiltrating CD3(+) and CD3(+)CD8(+) cells was studied in detail and the majority (90%) of these cells were shown to be functionally activated granzyme B-positive cytotoxic T cells. DNA oligotyping of a lung carcinoma cell line established from this tumor revealed loss of one HLA haplotype corresponding with a translocation involving chromosome 6, as observed by COBRA-FISH. HLA class I-restricted tumor specific T cells could be isolated from PBMC. One further characterized cytotoxic CD8(+) T cell clone, that released TNF-alpha, IFN-gamma, and granzyme B upon co-incubation with the autologous tumor cells, was shown to be restricted by the remaining HLA-A11 allele, which was also shown to be expressed in the tumor tissue. Our data indicate that, despite HLA-haplotype loss a vigorous antitumor immune response mediated by CD8(+ )T-cells can be present in NSCLC offering possibilities for specific immunotherapy.
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PMID:Functional CD8+ T cells infiltrate into nonsmall cell lung carcinoma. 1692 94

The aim of the present study was to elucidate the tumor-specific cellular immunological responses occurring in a patient with large cell carcinoma of the lung who had no evidence of recurrence following surgical resections of both a primary lung lesion and a metastatic adrenal lesion. We analyzed an autologous tumor-specific cytotoxic T lymphocytes (CTL clone F2b), which were HLA-A*2402 restricted from regional lymph node lymphocytes. The F2b possessed T cell receptor (TCR) using the Valpha5 and Vbeta7 gene segment. The existence of precursor CTL (pCTL) against autologous tumor cells (A904L) was analyzed using CTL clone-specific PCR. Lymphocytes with the same TCR as F2b were detected in the primary tumor tissue, regional lymph node and the peripheral blood collected from the patient 3 years after the operation. Using the F2b, we identified a cDNA clone encoding the tumor antigen using cDNA expression cloning method. The gene was found to encode splicing variant of the Tara gene. Finally, we identified the 9-mer Ag peptide, using constructions of mini-genes. The F2b recognized 3 out of 7 HLA-A24 positive allogeneic tumor cell lines and in 1 out of 7 HLA-A24 negative allogeneic tumor cell lines when transfected with HLA-A24. This peptide is therefore considered to be potentially useful for performing specific immunotherapy in a significant proportion of lung cancer patients bearing HLA-A24.
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PMID:Identification of HLA-A24 restricted shared antigen recognized by autologous cytotoxic T lymphocytes from a patient with large cell carcinoma of the lung. 1713 42


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