ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02570.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

For several years this laboratory has studied the expression of HLA class I on established colorectal tumor cell lines and on fresh tumors. We review here the mechanisms by which colorectal tumor cells may lose surface expression of HLA class I molecules. Several independent mechanisms have been identified, including loss or mutations in β2‐microglobulin genes, loss of HLA heavy chain genes, selective lack of expression of HLA alleles, and regulatory defects in HLA expression including loss of expression of the peptide transporters associated with antigen processing (TAP). The data suggest that colorectal tumor cells may evade tumor specific, HLA restricted immune attack by loss of HLA class I expression through a number of mechanis

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02571.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

A combination of immunohistochemical, biochemical, and recombinant DNA techniques were used to investigate class I expression in 26 pancreatic adenocarcinomas and 6 autologous tumor‐derived cells. The prevalence of HLA losses was found to be comparable to that observed in other tumor types (>35%), using monomorphic and locus‐specific antibodies. In one patient, the original tumor tissue, a tumor derived cell line (IMIM‐PC‐2), and EBV‐transformed lymphocytes were available for study. The patient's phenotype was A25, A30, B18, B18. However, A30 allele product could not be detected in the original tumor not in the cultured tumor cells. In addition, A30 allele could not be isolated from cDNA or genomic clones from the cultured tumor cells whereas it was isolated from the autologous lymphoblastoid cell line. Using isoelectric focusing analysis a significant reduction in the B18 heavy chain product was also observed in the tumor cell line, IMIM‐PC‐2, suggesting the absence of expression of one allele. Further studies revealed loss of heterozygosity at DR and other loci of chromosome 6 and cytogenetic data strongly suggested deletion of a full chromosome 6. This work indicates for the first time that loss of a full HLA haplotype occurs in tumor tissue and suggests that this mechanism may contribute to the progression of

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02572.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Analysis of melanoma cell lines with abnormalities in HLA Class I antigen expression has identified two serological phenotypes caused by distinct molecular defects. One is characterized by lack of HLA Class I antigen expression which is not induced by IFN‐γ or by incubation at 25°C for 24 hrs. This phenotype reflects structural changes in the β2m gene which interfere with its transcription and/or translation or result in the synthesis of a defective β2‐μ polypeptide unable to associate with HLA Class I heavy chains. The other phenotype manifests very low HLA Class I antigen expression which is enhanced by IFN‐γ or by incubation at 25°C for 24 hrs. This phenotype reflects abnormalities in TAP heterodimer expression, which cause defects in stable assembly and intracellular transport of the HLA Class I antigen trimolecular complex. Loss of HLA Class I antigens renders melanoma cells resistant to lysis by HLA Class I antigen‐restricted cytotoxic T cells which specifically recognize melanoma associated antigens. Therefore, abnormalities in HLA Class I antigen expression may have a negative impact on the outcome of T cell based immunotherapy. Characterization of the molecular defects underlying loss of HLA Class I antigens may suggest approaches to restore their expression. Inclusion of these approaches in the protocols of T cell based immunotherapy may improv

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02573.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

α/β and γ type interferons (IFN), act through distinct cell surface receptors and induce transcription of an overlapping sets of genes. MHC class I genes are inducible by both type of interferons. We have analyzed a gastric tumor cell line, AGS, which was completely defective in MHC class I response to interferon‐α and ‐γ. Northern blot analysis demonstrated that the lack of IFN response was related with the absence of up‐regulation of specific HLA class I mRNA. Electrophoretic mobility shift assays in various tumor cell lines after IFN‐α and IFN‐γ treatment showed differential binding of the transcriptional factors to MHC class I regulatory elements. Comparison of k‐B binding activity showed that IFN‐α and IFN‐γ induced opposite changes in NF‐kB binding activity in AGS cells, indicating that the absence of MHC class I response in AGS appears to be independent of k‐B activity. In contrast, there were remarkable differences in the level of transcriptional factor binding to an interferon‐responsive sequence element (IRSE), between AGS and other interferon‐responsive tumor cell lines. This result suggests that the low level of transcriptional factor binding to IRSE in AGS cells was responsible of the lack of induction of MHC class I antigens. In this context, overlapping factors in the signal transduction pathway of both type I and II interferons may be involved in the non‐responsiveness of this

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02574.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Variant cancer cells which arise from the parent tumor during tumor progression can escape immunity but retain antigens. We have mixed highly immunogenic (A+B+) murine parental cancer cells with less immunogenic (A‐B+) variant cancer cells to construct a model of a cancer containing escape variants. When such mixtures of cancer cells were injected into normal mice, the variant cells grew out because immune responsiveness to the B antigen on the variant was hindered by dominance of the A antigen on the surrounding parental tumor cells. However, A‐B+variant cells inoculated alone at a separate site induced B specific cytolytic T cells and were rejected. Moreover, mice immunized with A‐B+cells rejected a challenge which contained a mixture of variant and parental cancer cells, while immunization with A+B+cells was ineffective. Thus, variant tumor cells selected from parental tumor cells by cytolytic T cellsin vitrocan be used to induce protective immunity against variants expected to escape tumor immunityin vivo.The immunodominance of the A antigen may be related to its ability to induce a much more rapid CTL response than the B antigen, since we show in another model that the preexistence of a CTL response to one antigen prevented the subsequent induction of CTL to another antigen injected at the same site, even if both antigens were equally efficient at inducing CTL. These results indicate that immunodominance can affect strong as well as weak antigens. Vaccination with individual antigens at separate sites rather than with multiple antigens at one site may, therefore, be needed to prevent tumor escape and tumor recurrence or to counteract infectious dis

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02575.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Specific expression of the non classical class I HLA‐G gene on trophoblasts, the only fetal tissue in contact with maternal cells which lack MHC class I antigens, may indicate a role of this gene in fetal‐maternal tolerance. We recently reported HLA‐G transcription in peripheral blood leukocytes. In this work, we have investigated HLA‐G transcription in hematopoietic stem cells, in different hematopoietic lineages and in malignant cells by using a RT‐PCR technique. PCR amplification with primers specific to the exon 2 and the 3′ untranslated region has enabled to detect HLA‐G transcription in B and T cell populations. No transcription was found in CD34+ cells, in thymocytes, in polynuclear cells, in monocytes and in natural killer cells. Among the malignancies analyzed, HLA‐G is transcribed in 2 of 13 cases of acute leukemia characterized by a monocytic contingent, in 3 of 6 CLL and in all the cases of B‐NHL (n=6). No HLA‐G transcription was detected in myeloma (n=2). The splicing type does not seem to be linked to a lymphocyte subpopulation nor to a malignant proliferation stage. These results suggest that HLA‐G is a marker of mature lymphoid cells and may play an immunological function as a peptide presenting molecule. HLA‐G transcription in some cases of malignancy might indicate a contribution to the tumoral progression by blocking n

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02576.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Mouse tumor cells transfected with syngeneic MHC class II genes are highly immunogenic in the autologous host, and induce a potent tumor‐specific immunity against wild type tumor. Previous studies with sarcoma tumor cells expressing transfected class II gene products with truncated cytoplasmic domains suggested that during the process of tumor rejection costimulatory molecules are induced on the tumor cells, contributing to the cells' ability to stimulate immunity. In the present study we directly demonstrate that tumor cells containing full‐length class II heterodimers are induced to express B7–1 and B7–2 costimulatory molecules during the rejection process. In contrast, tumor cells expressing class II heterodimers truncated for their cytoplasmic tails are not induced to express B7–1 and/or B7–2. Blocking the interaction of the induced costimulatory molecules with their corresponding receptors on T cells prevents tumor rejection. These results support the hypothesis that the cytoplasmic domain of the MHC class II molecule is involved in induction of costimulatory molecule expression, perhaps via intracellular signalling pathways. Because class II, B7 transfected tumor cells are such effective immunogens against ascites and solid tumors, they have also been tested in metastatic disease. K1735 and B16BL6 mouse melanomas, when transfected with syngeneic MHC class II and B7–1 genes, are significantly less metastatic than parental cells, and immunization with the transfectants protects against subsequent challenge with wi

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02577.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02578.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02579.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY