MHC class II‐deficient tumor cell lines with a defective expression of the class II transactivator

Naves, Rodrigo; Lennon, Ana Maria; Barbieri, Giovanna; Reyes, Lilian I.; Puga, Gisella; Salas, Laura; Deffrennes, Virginie; Rosemblatt, Mario; Fellous, Marc; Charron, Dominique; Alcaïde‐Loridan, Catherine; Bono, Marı́a Rosa

doi:10.1093/intimm/14.5.481

Cited by 9 publications

(14 citation statements)

References 49 publications

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Section: Ciita Silencing In Tumor Cellsmentioning

confidence: 99%

“…Moreover, the inability to induce MHCII expression in response to IFN-+ is often associated with tumor cells of non-hematopoietic origin [58,[95][96][97][98][99][100]. There is growing evidence that this inability to express MHCII results from epigenetic silencing of the MHC2TA gene [95][96][97][98][99][100][101][102]. The regulatory regions of the MHC2TA gene have been found to be hypermethylated at CpG dinucleotides in MHCII -T cell leukemias, B cell lymphomas and various tumor cells that are unable to express MHCII upon exposure to IFN-+ , including teratocarcinoma, choriocarcinoma, neuroblastoma, erythroleukemia and small cell lung cancer [95,97,[100][101][102].…”

Section: Ciita Silencing In Tumor Cellsmentioning

confidence: 99%

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Mini‐review: Specificity and expression of CIITA, the master regulator of MHC class II genes

et al. 2004

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The class II transactivator (CIITA) has been referred to as the "master control factor" for the expression of MHC class II (MHCII) genes. As our knowledge on the specificity and function of CIITA grows, it is becoming increasingly evident that this sobriquet is entirely justified. First, despite extensive investigations, the major target genes of CIITA remain those implicated in the presentation of antigenic peptides by MHCII molecules. Although other putative target genes have been reported, the contribution of CIITA to their expression remains indirect, controversial or comparatively minor relative to its decisive role as a regulator of MHCII and related genes. Second, the most important parameter dictating MHCII expression is by far the expression pattern of the gene encoding CIITA (MHC2TA). The vast majority of signals that activate or repress MHCII expression under physiological and pathological situations converge on one or more of the three alternative promoters that drive transcription of the MHC2TA gene. In short, with respect to its specificity and its exquisitely controlled pattern of expression, CIITA is by a long stretch the single most important transcription factor for the regulation of genes required for MHCII-restricted antigen-presentation.

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Section: Ciita Silencing In Tumor Cellsmentioning

confidence: 99%

Section: Ciita Silencing In Tumor Cellsmentioning

confidence: 99%

Mini‐review: Specificity and expression of CIITA, the master regulator of MHC class II genes

et al. 2004

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“…Defects in one or more factors, such as the class II transactivator (CIITA), required for transcription of HLA class II and Ii, have been reported in various carcinoma cell lines that do not upregulate HLA class II expression. 32,33 It would be surprising, however, if defective CIITA was more frequent in DRB1*07 tumors, but the effect could be indirect since CIITA activation in tumor cells requires IFN-␥, whose effects are known to be inhibited by TGF-␤. 34 Thus, if DRB1*07 tumors preferentially stimulate immunosuppressive T cells, it could explain poor tumor cell expression of all DR allotypes as well as Ii, despite the presence of infiltrating T cells.…”

Section: Hla-dr ϩ Tumor Cells Discordantly Express Hla-drb Allelic Prmentioning

confidence: 99%

HLA‐DRB alleles are differentially expressed by tumor cells in breast carcinoma

Oldford

Robb

Watson

et al. 2004

Intl Journal of Cancer

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The biologic and prognostic significance of HLA-DR expression and T-cell infiltration in breast carcinoma are presently controversial. To test the hypothesis that these factors are influenced by particular HLA-DRB alleles, 52 breast tumor samples, composed of 26 DRB1*04 and 26 non-DRB1*04 tumors, were assessed using immunohistochemistry for expression of DR and its associated invariant chain (Ii) and for infiltrating CD3 ؉ T cells. While DR expression by tumor cells was significantly associated with T-cell infiltration, DRB1*04 tumors were more frequently DR ؉ Ii ؉ and contained smaller CD3 ؉ infiltrates than non-DRB1*04 tumors. This difference was largely attributable to DRB1*07 tumors, which were typically DR ؊ Ii ؊ , although they contained similar numbers of T cells to DR ؉ Ii ؉ tumors. Further analysis of DR ؉ tumors using allotype discriminating antibodies revealed that DRB1*04 alleles were always expressed, while non-DRB1*04 alleles were inconsistently expressed. The results of this study provide the first reported evidence that DRB alleles influence DR expression and T-cell infiltration in breast carcinoma and suggest that multiple factors contribute to DR expression. Ongoing studies aimed at elucidating the molecular and immunologic mechanisms controlling differential DR expression and implications for prognosis and outcome should further our understanding of the antitumor immune response and evasion strategies employed by tumor cells. © 2004 Wiley-Liss, Inc. Key words: HLA-DR expression; HLA-DRB alleles; T-cell infiltration; breast carcinoma; invariant chainA prerequisite for tumor eradication by CD8 ϩ cytolytic T cells is recognition of tumor antigen presented by HLA class I molecules on the tumor cells and this is reflected by the numerous studies showing loss or downregulation of HLA class I on established tumors. 1,2 Optimal antitumor immunity also requires participation of CD4 ϩ T cells, which recognize tumor peptides presented by HLA class II molecules (HLA-DR, -DP, -DQ). [3][4][5] However, the importance of HLA class II expression on breast carcinoma cells and implications for antitumor immunity are currently unclear. Unlike HLA class I, HLA class II molecules are not normally present on resting epithelial cells, although they are detected de novo in the lactating breast and in a subset of breast carcinomas. 6 They can also be induced in vitro on many cell types, including breast cancer cell lines, by interferon-␥ (IFN-␥) 7,8 and other immunomodulators, 9,10 suggesting that in situ expression on carcinoma cells may be regulated by cytokines and/or hormones. Antigen presentation by HLA class II ϩ breast cancer cells, which lack costimulatory molecules typically found on professional antigen presenting cells (APCs), could potentially induce T-cell anergy. However, reports of direct recognition of tumor cells by HLA class II-restricted CD4 ϩ T cells 11,12 suggest that HLA class II ϩ tumor cells play an important role in determining the outcome of an antitumor immune response.Studies investigating e...

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“…24,[26][27][28] One can wonder if this indicates that the alteration of CIITA expression can provide an advantage to the tumor cells. A hypothesis is that the loss of CIITA expression might favor tumor proliferation or resistance to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Defective class II transactivator expression in a B lymphoma cell line

et al. 2004

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Loss of MHC class II expression in B-cell lymphoma has been associated with a higher tumorigenicity resulting from lower titers of tumor-infiltrating lymphocytes. This report aims towards the identification of the molecular mechanism leading to defective MHC class II expression in a B-cell lymphoma cell line, Rec-1. We evidenced a coordinated alteration of HLA-D gene transcription, reminiscent of B lymphoblastoid cell lines from patients with MHC class II deficiency. Genetic complementation performed between these cell lines and the lymphoma cells indicated that Rec-1 is altered in the MHC2TA gene. MHC2TA encodes the class II transactivator (CIITA), the master regulator of HLA-D gene expression. However, the coding sequence of the Rec-1 CIITA transcript did not reveal any mutation that could hamper the activity of the encoded protein.In agreement with the genetic complementation analysis, we evidenced a highly residual CIITA protein expression in the Rec-1 cell line resulting from a transcriptional defect affecting MHC2TA expression. Anti-HLA-DR monoclonal antibody treatment has proved efficient in the destruction of B lymphoma cells. Our data indicate that the appearance of variants losing CIITA, and thereby HLA-DR, expression will require a thorough monitoring during such immunotherapy protocols.

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MHC class II‐deficient tumor cell lines with a defective expression of the class II transactivator

Cited by 9 publications

References 49 publications

Mini‐review: Specificity and expression of CIITA, the master regulator of MHC class II genes

Mini‐review: Specificity and expression of CIITA, the master regulator of MHC class II genes

HLA‐DRB alleles are differentially expressed by tumor cells in breast carcinoma

Defective class II transactivator expression in a B lymphoma cell line

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