High frequency of altered HLA class I phenotypes in invasive breast carcinomas

Cabrera, Teresa; Fernández, María Angustias Parejo; Sierra, Àngels; Garrido, António; Herruzo, A; Escobedo, A.; Fabra, Àngels; Garrido, Federico

doi:10.1016/0198-8859(96)00145-0

Cited by 124 publications

(81 citation statements)

References 24 publications

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“…Indeed, the degree of HLA class I loss is likely underestimated as most tumors classified as HLA class I ϩ using the W6/32 mAb do indeed contain altered HLA class I phenotypes. 44 The small sample size and biased selection for DRB1*04 in this study preclude a meaningful statistical analysis of tumor cell expression of DR and Ii and T-cell infiltration with prognostic indicators. However, there were some notable trends such as reduced ER levels in non-DRB1*04 tumors that expressed DR and Ii compared to ER levels in DRB1*04 DR ϩ tumors, suggesting that ER may be implicated in regulating DR expression in these tumors.…”

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

confidence: 89%

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

confidence: 89%

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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“…On the other hand, the increased susceptibility of HLA class I-negative tumours to lysis by NK cells may influence metastatic potential and survival (Karre et al, 1986), and finally, selective losses of HLA class I allelic products on tumours with positive expression for HLA-A, -B and -C antigens may frequently be present and also influence the metastatic potential (Honma et al, 1994). Our group is currently investigating HLA phenotype in invasive breast carcinomas using anti-HLA polymorphic antibodies, and more than 88.5% of the tumours showed an altered HLA tumour phenotype, when compared with the peripheral blood lymphocytes of each patient (Cabrera et al, 1996). In that paper, HLA-ABC total losses were found in a similar proportion to those in laryngeal carcinomas; however, it seems that those laryngeal tumours presenting 'normal' expression of HLA class I antigens could have allelic losses not shown with the MAbs used in our 1990 study, as demonstrated in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

MHC class I antigens and tumour-infiltrating leucocytes in laryngeal cancer: long-term follow-up

Esteban

Redondo²,

Delgado³

et al. 1996

Br J Cancer

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Summary Alteration in MHC class I expression may be used by cancer cells to avoid immune destruction. Much experimental evidence supports this idea, although survival studies are very scarce. To investigate whether the presence or absence of HLA-A, -B and -C antigens in laryngeal carcinoma influences survival, a series of 60 primary laryngeal tumours treated surgically and normal tissues were evaluated in frozen sections for the expression of MHC class I antigens and tumour-infiltrating leucocytes (CD3, CD4, CD8, CD1Ib, CD1, CD20 and CDI6), using monoclonal antibodies and the APAAP technique. Long-term follow-up from the patients is available, ranging from 6 to 10 years. Thirteen tumours presented total HLA-ABC loss, five selective losses of HLA-A antigens and one absence of HLA-B antigens. Total losses were statistically associated with several clinical and pathological parameters, but there were no differences regarding tumour-infiltrating leucocytes. After conducting a prospective study, only T and N staging and scoring according to Glanz's malignancy classification were found to be independently related to patients' outcome. From our data, we conclude that neither complete loss of HLA class I antigens nor tumour-infiltrating leucocytes appear to influence survival in squamous cell carcinoma of the larynx.

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“…It is difficult to define the precise frequency of tumors that show loss of expression of only one HLA allele because of deficits in the repertoire of allele specific antibodies. The use of a wide set of mAbs against individual HLA alleles shows that selective allele down regulation, not categorized as phenotypes I-III, is observed in many tumors (15%-51%) [33,34]. Such allelic loss might result from point mutations, partial deletions of HLA class I genes, or as a consequence of chromosomal breakage or somatic recombination.…”

Section: Phenotype IVmentioning

confidence: 99%

The HLA crossroad in tumor immunology

Algarra¹,

Cabrera²,

Garrido³

2000

Human Immunology

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134

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ABSTRACT:It is generally accepted that human and experimental tumor cells can lose major histocompatibility complex (MHC) class I molecules. These human leukocyte antigen (HLA) losses are detected when the primary tumor breaks the basal membrane, invades the surrounding tissues, and starts to metastasize. These altered HLA class I phenotypes probably constitute the major tumor escape mechanism facing anti-tumor T-cell mediated responses. Thus, it is important to characterize these phenotypes in clinical tumor samples, analyze the mechanism(s) responsible for them, and counsel patients before and during peptide anti-cancer immunotherapy. The present paper summarizes the most relevant altered HLA class I phenotypes found in human tumor samples, indicates their frequency, and outlines the mechanisms implicated. This review also points out that the natural killer (NK) escape mechanism of HLA class I deficient cancer cells is yet to be defined. Knowledge accumulated to date reveals that HLA class I molecules are an important crossroad in tumor immunology. Human Immunology 61, 65-73 (2000).

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High frequency of altered HLA class I phenotypes in invasive breast carcinomas

Cited by 124 publications

References 24 publications

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

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

MHC class I antigens and tumour-infiltrating leucocytes in laryngeal cancer: long-term follow-up

The HLA crossroad in tumor immunology

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