Relevance of the immune system in human urological malignancies: prospective for future clinical treatments

Nouri, A. M. E.; Symes, M. O.

doi:10.1016/s0090-4295(98)00073-9

Cited by 6 publications

(6 citation statements)

References 77 publications

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“…Activation of certain oncogenes may block transcription of the B locus [20], and in some cases this may in turn affect only the HLA-B44 allele. In the present study HLA-B locus antigens tended to be more defective than HLA-A locus antigens, a finding also reported by others [21].…”

Section: Discussionsupporting

confidence: 92%

High frequency of HLA-B44 allelic losses in human solid tumors

et al. 2003

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Human leukocyte antigen (HLA) class I downregulation, a frequent phenomenon observed in a variety of human tumors, favors tumor immune escape from T-lymphocyte recognition. However, it is not known whether a particular HLA class I allele is lost more frequently than others. To address this question we analyzed HLA class I expression in tumor tissues derived from 300 patients diagnosed as having breast, colorectal, or laryngeal carcinomas. Cryostatic tumor sections and a broad panel of anti-HLA class I monoclonal antibodies were used. We found that the HLA-B44 allele was lost more frequently than other HLA class I alleles, and that the difference was not related with changes in HLA-B44 allele frequencies between patients and controls. In addition, we observed that 35% of the HLA-B44 negative tumors presented HLA haplotype loss associated with loss of heterozygosity. These tests were performed on DNA samples obtained from microdissected tumor tissues. The results seem to indicate that HLA class I allelic losses are not randomly distributed during tumor development but that some HLA class I alleles, and HLA-B44 in particular, are more frequently downregulated and may play an important role in immune escape mechanisms. Human Immunology 64, 941-950 (2003).

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Section: Discussionsupporting

confidence: 92%

High frequency of HLA-B44 allelic losses in human solid tumors

et al. 2003

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“…One of the clinically well-established immunotherapies is Bacillus CalmetteGué rin (BCG) bacterial instillation for the treatment of urinary bladder carcinoma (Alexandroff et al 1999). However, the tumour often relapses and, although instillation of BCG evokes an inflammtory response, it is inefficient in activating tumour-specific cytotoxic T cells (CTLs) (Ratliff et al 1993, Nouri & Symes 1998. CTLs are the most potent tumour killer cells as exemplified by graft-versus-host reactions in allogeneic stem cell transplantation, which is an accepted curative therapy for patients with chronic myeloid leukaemia (Kessels et al 2002).…”

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confidence: 99%

Optimization of the MB49 mouse bladder cancer model for adenoviral gene therapy

et al. 2005

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SummaryBladder cancer is regarded as a promising candidate for innovative therapies in the field of immune and gene therapy. In this paper, we present the subcutaneous, metastatic and a novel orthotopic model of murine MB49 bladder cancer in C57BL/6 mice. We further show the potential of using adenoviral vectors together with different transduction enhancers to augment in vivo gene delivery. Finally, we present candidate genes for tumour detection, therapy or targeting.The MB49 tumour grew rapidly in mice. The subcutaneous model allowed for tumour detection within a week and the possibility to monitor growth rate on a day-by-day basis. Injection of MB49 cells intravenously into the tail vein gave rise to lung metastases within 16 days, while instillation of tumour cells into pretreated bladders led to a survival time of 20-40 days. Adenoviral vectors can be used as a vehicle for gene transfer to the bladder. By far, the most potent transduction enhancer was Clorpactin, also known as oxychlorosene. Last, we show that MB49 cells express tumour-associated antigens like bladder cancer-4, prostate stem cell antigen and six-transmembrane epithelial antigen of the prostate.Given the possibility for efficient genetic modification of the bladder and the presence of known tumour antigens, the MB49 models can be used in innovative ways to explore immunogene therapy.

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“…Malignant transformation of the urothelium involves several phenotypic changes on the cell surface, such as the loss of normally expressed molecules: MHC antigens, cellular adhesion molecules and blood group antigens 14. Total HLA class I antigen loss has been reported in TCC at frequencies that range from 8%15 to 42%,16, 17, and this was correlated with the degree of tumor differentiation and the survival 16. However, there is little information regarding the molecular mechanisms of HLA class I antigen loss in TCC.…”

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confidence: 99%

Coordinated downregulation of the antigen presentation machinery and HLA class I/β2-microglobulin complex is responsible for HLA-ABC loss in bladder cancer

et al. 2004

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Key words: HLA; ␤2m; antigen processing machinery; bladder carcinoma; tumor escape Downregulation of HLA class I molecules is a frequent event observed in human tumors, and it is believed to be related with tumor immune escape. Several types of HLA class I downregulation have been described including total, locus, allele and haplotype loss. 1 Total HLA class I loss is a relatively frequent phenotype (9 -52%) detected in tumors derived from different tissues such as melanoma, head-neck, colorectal, prostate and breast cancer. 2 Molecular mechanisms that have been shown to be responsible for this phenotype include the following. 1) ␤2-microglobulin (␤2-m) gene mutations, which play an important role in assembly of the HLA complex (HLA heavy chain, ␤2-m and peptide). ␤2-microglobulin gene mutations result in failure to assemble the class I molecules for cell surface expression and are therefore responsible for total HLA class I loss. Frequent ␤2-m mutations have been described in colorectal and gastric cancers of the microsatellite mutator phenotype (MMP), 3,4 which exhibit a type of genetic instability characterized by the accumulation of somatic mutations in repeated sequences. 5 The ␤2-m gene contains several repeat sequences and so is a mutational target for mismatch repair deficiency. The frequency of ␤2-m mutations in other tumor types that infrequently display MMP (breast cancer and melanoma) is lower than in colorectal carcinomas. 3 2) Downregulation of proteins involved in the antigen processing pathway is responsible for total HLA class I loss due to a deficiency in peptide formation, loading of MHC molecules and transport. MHC class I presentation of peptides is a multistep process involving several molecules: catalytic ␤ subunits of the proteasome (LMP2, LMP7 and LMP10), transporter associated with antigen processing (TAP-1 and TAP-2) and various endoplasmic reticulum chaperones. Numerous studies have demonstrated deficiencies in the expression of antigen-processing genes in tumor cell lines. 6 -10 Most of the deficits described are combined deficiencies comprising multiple components, 6,9,10 though selective deficiencies have also been described. 7,10 Most of these alterations are corrected by cytokine treatment, particularly by IFNgamma. In contrast, structural defects in antigen-processing genes are very uncommon and only 2 point mutations in TAP-1 gene have been described. 11,12 3) Finally, hypermethylation of HLA class I promotor genes can also repress HLA class I expression, as has been demonstrated in melanoma cell lines. 13 Although HLA class I total loss can be found in histologically different tumor types, carcinogenesis in each tissue present particular characteristics. In despite of the great advances in our knowledge of molecular lesions that produce HLA class I total loss in tumor cell lines, in some particular human tumor tissues the underlying mechanisms remain to be established.Bladder cancer is one of the most common malignancies worldwide, with transitional cell carcinoma (TCC) being ...

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Relevance of the immune system in human urological malignancies: prospective for future clinical treatments

Cited by 6 publications

References 77 publications

High frequency of HLA-B44 allelic losses in human solid tumors

High frequency of HLA-B44 allelic losses in human solid tumors

Optimization of the MB49 mouse bladder cancer model for adenoviral gene therapy

Coordinated downregulation of the antigen presentation machinery and HLA class I/β2-microglobulin complex is responsible for HLA-ABC loss in bladder cancer

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