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)

Small cellular lung carcinoma (SCLC) cell lines are susceptible to lysis by NK cells. SCLC, normally negative for MHC class I Ag, were rendered positive for HLA-A and -B Ag by two methods: treatment with IFN-gamma or transfection with HLA class I genes. Exposure to IFN-gamma induced high levels of class I Ag and reduced susceptibility to NK-mediated lysis. However, transfection with either HLA-A2, HLA-B27, or HLA-B27 with beta 2m did not result in reduced susceptibility to NK cells. These transfectants expressed amounts of HLA class I Ag comparable to those in IFN-gamma-treated, untransfected cells. Transfection with the beta 2m gene or plasmid alone neither influenced levels of surface class I Ag nor resulted in reduced susceptibility to lysis by NK cells. Thus, the effects of IFN-gamma on NK susceptibility can be dissociated from the induction of class I Ag.
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PMID:Lack of correlation between levels of MHC class I antigen and susceptibility to lysis of small cellular lung carcinoma (SCLC) by natural killer cells. 254 Dec 6

Previous studies have identified and characterized both murine in vivo and human in vitro T cell responses reflecting specific mutations in the ras proto-oncogenes at codon 12, 13, or 61. In an attempt to determine whether peptide epitopes reflecting point mutations in the ras oncogenes are immunogenic in humans for the production of CD4+ and/or CD8+ T cell responses, a phase I clinical trial was initiated in metastatic carcinoma patients whose primary tumors harbor mutations in the K-ras proto-oncogenes at codon 12. The peptides used here as immunogens, which were administered in Detox adjuvant, spanned the ras sequence 5-17 and reflected the amino acid substitution of glycine (Gly) at position 12 to aspartic acid (Asp), cysteine (Cys), or valine (Val). Three of eight evaluable patients have demonstrated peptide-specific cell-mediated immunity, as determined by the production of T cell lines resulting from the vaccination. First, an antigen (Ag)-specific, major histocompatibility complex (MHC) class II (DP)-restricted CD4+ T cell line was established in vitro from postvaccination lymphocytes of a non-small cell lung carcinoma patient whose primary tumor contained a Cys12 mutation when cultured on the immunizing peptide. Moreover, CD4+ proliferation was inducible against the corresponding mutant K-ras protein, suggesting productive T cell receptor recognition of exogenously processed Ag. Second, an Ag-specific, MHC class I (HLA-A2)-restricted CD8+ cytotoxic T lymphocyte (CTL) line was established in vitro from postvaccination lymphocytes of a colon carcinoma patient whose primary tumor contained an Asp12 mutation. To that end, a 10-mer peptide, nested within the 13-mer immunizing peptide, was identified [i.e., ras5-14(Asp12)], which was shown to bind to HLA-A2 and display specific functional capacity for expansion of the in vivo primed CD8+ CTL precursors. Third, both Ag-specific, MHC class II (DQ)-restricted CD4+ and MHC class I-restricted (HLA-A2) CD8+ T cell lines were generated from a single patient with duodenal carcinoma whose primary tumor contained a Val12 mutation when cultured on the immunizing 13-mer peptide or a nested 10-mer peptide [i.e., ras5-14(Val12)], respectively. Evidence is thus provided that vaccination with mutant ras oncogene peptides in adjuvant may induce specific anti-ras cellular immune responses, with no detectable cross-reactivity toward normal proto-ras sequences. Moreover, we have identified for the first time human HLA-A2-restricted, CD8+ CTL epitopes reflecting specific point mutations in the K-ras oncogenes at codon 12 which, in concert with the activation of the CD4+ T cell response, may have important implications for both active and passive immunotherapies in selected cancer patients.
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PMID:Generation of stable CD4+ and CD8+ T cell lines from patients immunized with ras oncogene-derived peptides reflecting codon 12 mutations. 951 98

Melanoma tumor antigens, MAGE-1 and -3 are presented on HLA-A1 and -Cw*1601, or -A1 and -A2, respectively, to the corresponding cytotoxic T lymphocytes (CTL). If CTL recognizing these antigens were generated in patients, clones of positive tumor cells should be eliminated. To ascertain whether such an immunological response is active in patients with lung cancer and to determine what fraction of lung cancer patients are candidates for MAGE oriented immunotherapy, we assessed the relationship between HLA-A1 or -A2 expression and MAGE-1 or -3 gene expression in their tumors. MAGE-1 and -3 were detected in 18/55 (33%) and 23/55 (42%), respectively, by reverse transcriptase (RT)-polymerase chain reaction (PCR). Allele specific PCR revealed HLA-A1 and -A2 alleles to be expressed in 0/55 (0%) and 22/55 (40%) of our cohort, respectively. Among the 22 patients with HLA-A2 genotype, expression of HLA class I antigens detectable by immunohistochemistry was lost in five (23%) cases. The frequency of MAGE-3 expression in HLA-A2 patients was 5/17 (29%), somewhat lower than that of patients without HLA-A2 expression, 18/38 (47%), although the difference was not statistically significant (P = 0.17). Neither was there a significant association between HLA-A2/MAGE-3 co-expression and survival (P = 0.15, logrank test). We conclude that there is no clear evidence for elimination of lung cancers co-expressing HLA-A2 and MAGE-3 in vivo. Approximately 10% (5/55) of Japanese lung cancer patients are potential candidates for MAGE-3-based immunotherapy.
Lung Cancer 1998 May
PMID:Frequency of MAGE-3 gene expression in HLA-A2 positive patients with non-small cell lung cancer. 971 30

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

We have identified an antigen recognized by autologous CTL on the lung carcinoma cells of a patient who enjoyed a favorable clinical evolution, being alive 10 years after partial resection of the primary tumor. The antigenic peptide is presented by HLA-A2 molecules and encoded by a mutated sequence in the gene coding for malic enzyme, an essential enzyme that converts malate to pyruvate. In the tumor cell line derived from the patient, only the mutated malic enzyme allele is expressed, because of a loss of heterozygosity in the region of chromosome 6 that contains this locus. Tetramers of soluble HLA-A2 molecules loaded with the antigenic peptide stained approximately 0.4% of the patient's blood CD8 T cells. When these cells were stimulated in clonal conditions, 25% of them proliferated, and the resulting clones were lytic and specific for the mutated malic enzyme peptide. T-cell receptor analysis indicated that almost all of these antimalic CTLs shared the same receptor. Antimalic T cells were consistently found in blood samples collected from the patient between 1990 and 1999, at frequencies ranging from 0.1 to 0.4% of the CD8 cells. Their frequency appeared to double within 2 weeks after intradermal inoculation of lethally irradiated autologous tumor cells. These results indicate that nonmelanoma cancer patients may also have a high frequency of blood CTLs directed against a tumor-specific antigen.
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PMID:High frequency of cytolytic T lymphocytes directed against a tumor-specific mutated antigen detectable with HLA tetramers in the blood of a lung carcinoma patient with long survival. 1132 44

We have identified an antigen recognized on a human large cell carcinoma by an autologous tumor-specific CTL clone that was derived from mononuclear cells infiltrating the primary tumor. The antigenic peptide is presented by HLA-A2 molecules and is encoded by the alpha-actinin-4 gene, which is expressed ubiquitously. In the tumor cells, a point mutation generates an amino-acid change that is essential for recognition by the CTLS: The mutation was not found in alpha-actinin-4 cDNA sequences from about 50 lung carcinoma cell lines, suggesting that it is unique to this patient. Although he did not receive chemotherapy or radiotherapy, the patient has been without evidence of tumor since the resection of the primary lesion in 1996. Using tetramers of soluble HLA-A2 molecules loaded with the mutated antigenic peptide, anti-alpha-actinin-4 CTLs could be derived from blood samples collected from the patient in 1998 and 2000. It is possible that these CTLs, recognizing a truly tumor-specific antigen, play a role in the clinical evolution of this lung cancer patient.
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PMID:A point mutation in the alpha-actinin-4 gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human lung carcinoma. 1135 29

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

We have previously identified an antigen (Ag) recognized on a human large cell carcinoma of the lung by a tumor-specific cytotoxic T lymphocyte clone derived from autologous tumor infiltrating lymphocytes (TILs). The antigenic peptide is presented by HLA-A2 molecules and is encoded by a mutated alpha-actinin-4 (ACTN4) gene. In the present report, we have isolated two anti-alpha-actinin-4 T cell clones from the same patient TIL and from his peripheral blood lymphocytes (PBLs) by using tetramers of soluble HLA-A2 molecules loaded with the mutated peptide. Although all of the clones displayed similar tetramer labeling, those isolated from PBL showed lower avidity of Ag recognition and killed the specific target much less efficiently, indicating that tetramer staining does not correlate with clone avidity/tumor reactivity. T cell receptor (TCR) analysis revealed that alpha-actinin-4-reactive clones used distinct alpha and beta chain rearrangements, demonstrating TCR repertoire diversity. Interestingly, TCR beta chain gene usage indicated that only Ag-specific clones with high functional avidity were expanded at the tumor site, whereas a low-avidity clone was exclusively amplified in patient peripheral blood. Our results point to the existence of distinct but overlapping antitumor TCR repertoires in TIL and PBL and suggest a selective in situ expansion of tumor-specific cytotoxic T lymphocyte with high avidity/tumor reactivity.
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PMID:Cytotoxic T lymphocytes directed against a tumor-specific mutated antigen display similar HLA tetramer binding but distinct functional avidity and tissue distribution. 1209 15

In the present report, we have investigated TRAIL/APO2 ligand (APO2L) expression, regulation, and function in human lung carcinoma tumor-infiltrating lymphocytes. Using a panel of non-small cell lung carcinoma cell lines, we first showed that most of them expressed TRAIL-R1/DR4, TRAIL-R2/DR5, but not TRAIL-R3/DcR1 and TRAIL-R4/DcR2, and were susceptible to APO2L/TRAIL-induced cell death. Two APO2L/TRAIL-sensitive tumor cell lines (MHC class I(+)/II(+) or I(+)/II(-)) were selected and specific CD4(+) HLA-DR- or CD8(+) HLA-A2-restricted CTL clones were respectively isolated from autologous tumor-infiltrating lymphocytes. Interestingly, although the established T cell clones did not constitutively express detectable levels of APO2L/TRAIL, engagement of their TCR via activation with specific tumor cells selectively induced profound APO2L/TRAIL expression on the CD4(+), but not on the CD8(+), CTL clones. Furthermore, as opposed to the CD8(+) CTL clone which mainly used granule exocytosis pathway, the CD4(+) CTL clone lysed the specific target via both perforin/granzymes and APO2L/TRAIL-mediated mechanisms. The latter cytotoxicity correlated with APO2L/TRAIL expression and was significantly enhanced in the presence of IFN-alpha. More interestingly, in vivo studies performed in SCID/nonobese diabetic mice transplanted with autologous tumor and transferred with the specific CD4(+) CTL clone in combination with IFN-alpha resulted in an important APO2L/TRAIL-mediated tumor growth inhibition, which was prohibited by soluble TRAIL-R2. Our findings suggest that APO2L/TRAIL, specifically induced by autologous tumor and up-regulated by IFN-alpha, may be a key mediator of tumor-specific CD4(+) CTL-mediated cell death and point to a potent role of this T cell subset in tumor growth control.
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PMID:Tumor-infiltrating CD4+ T lymphocytes express APO2 ligand (APO2L)/TRAIL upon specific stimulation with autologous lung carcinoma cells: role of IFN-alpha on APO2L/TRAIL expression and -mediated cytotoxicity. 1209 84

We have isolated several cytotoxic T lymphocyte (CTL) clones from lymphocytes infiltrating a lung carcinoma of a patient with long survival. These clones showed a CD3+, CD8+, CD4-, CD28- phenotype and expressed a T-cell receptor (TCR) encoded either by Vbeta8-Jbeta1.5 or Vbeta22-Jbeta1.4 rearrangements. Functional studies indicated that these clones mediated a high human leukocyte antigen (HLA)-A2.1-restricted cytotoxic activity against the autologous tumor cell line. Interestingly, TCRbeta chain gene usage indicated that CTL clones identified in vitro were selectively expanded in vivo at the tumor site as compared to autologous peripheral blood lymphocytes (PBL). These findings provide evidence that an immune response may take place in non-small cell lung carcinoma and that effector T cells may contribute to tumor regression. Further study indicated that the CTL clones recognized the same decamer peptide encoded by a mutated alpha-actinin-4 gene. Using tetramers of soluble HLA-A2 molecules loaded with the mutated antigenic peptide, we have derived several anti-alpha-actinin-4 T-cell clones from patient PBL. These CTL, recognizing a truly tumor-specific antigen, may play a role in the clinical evolution of this lung cancer patient. Adoptive transfer of CTL clones in a SCID/NOD mice model transplanted with autologous tumor supported their antitumor effect in vivo.
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PMID:Antitumor cytotoxic T-lymphocyte response in human lung carcinoma: identification of a tumor-associated antigen. 1244 85


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