Analysis of HLA-E expression in human tumors

Marín, Rosario; Ruiz‐Cabello, Francisco; Pedrinaci, Susana; Méndez, Rosa; Jiménez, Pilar; Geraghty, Daniel E.; Garrido, Federico

doi:10.1007/s00251-002-0526-9

Cited by 150 publications

(111 citation statements)

References 36 publications

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“…A target showing resistance to the HLA-I mediated immune response in a tumor could exhibit a raised HLA-G response and it has been postulated that abnormal expression of nonclassical HLA molecules may be required to inhibit the signal to natural killer (NK) cells, making the neoplastic cells resist lysis and enabling them to avoid detection by the immune system [21]. Tumors can follow a number of paths to escape from NK cells [35] and thus both of these molecules could work together to keep the tumor cells alive within their microenvironment, favoring their proliferation and malignant progression.…”

Section: Discussionmentioning

confidence: 99%

“…The expression of HLA-E had been expected to rise alongside that of HLA-G, as had occurred previously in cells transformed by cytomegalovirus [36]. HLA-E is normally transcribed in various tissues, but is expressed weakly on the surface of the cells, where its stability depends on the coexpression of HLA-C, HLA-G, and HLA-A molecules [35]. The normal expression of class I HLA molecules allows the HLA-E complex to become stable and thus be expressed more strongly [35].…”

Section: Discussionmentioning

confidence: 99%

“…HLA-E is normally transcribed in various tissues, but is expressed weakly on the surface of the cells, where its stability depends on the coexpression of HLA-C, HLA-G, and HLA-A molecules [35]. The normal expression of class I HLA molecules allows the HLA-E complex to become stable and thus be expressed more strongly [35]. It was evident in our study that the fall in HLA-I expression, followed by overexpression of HLA-G, resulted in the inhibition of HLA-E expression.…”

Section: Discussionmentioning

confidence: 99%

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Expression of the Classical and Nonclassical HLA Molecules in Breast Cancer

Silva

Duarte

et al. 2013

International Journal of Breast Cancer

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Considering that downregulation of HLA expression could represent a potential mechanism for breast carcinogenesis and metastasis, the aim of the present study was to use immunohistochemical methods to analyze the expression of HLA-Ia, HLA-DR, HLA-DQ, HLA-E, and HLA-G in invasive ductal carcinoma (IDC) of the breast and to relate this HLA profile to anatomopathological parameters. Fifty-two IDC from breast biopsies were stratified according to histological differentiation (well, moderately, and poorly differentiated) and to the presence of metastases in axillary lymph nodes. The expression of HLA molecules was assessed by immunohistochemistry, using a computer-assisted system. Overall, 31 (59.6%) out of the 52 IDC breast biopsies exhibited high expression of HLA-G, but only 14 (26.9%) showed high expression of HLA-E. A large number (41, 78.8%) of the biopsies showed low expression of HLA-Ia, while 45 (86.5%) showed high expression of HLA-DQ and 36 (69.2%) underexpressed HLA-DR. Moreover, 24 (41.2%) of 52 biopsies had both low HLA-Ia expression and high HLA-G expression, while 11 (21.2%) had low HLA-Ia expression and high HLA-E expression. These results suggest that, by different mechanisms, the downregulation of HLA-Ia, HLA-E, and HLA-DR and the upregulation of HLA-G and HLA-DQ are associated with immune response evasion and breast cancer aggressiveness.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Expression of the Classical and Nonclassical HLA Molecules in Breast Cancer

Silva

Duarte

et al. 2013

International Journal of Breast Cancer

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“…Previously, increased expression of HLA-E in several malignant cell types was described in combination with down-regulation of other HLA class I proteins [22,32]. HLA-E function has been investigated in the context of HPV, hepatitis C virus, human cytomegalovirus, human immunodeficiency virus, Epstein-Barr virus, and influenza virus infections [22], leading to the hypothesis that viral peptides are bind to HLA-E, upregulate its surface expression, and lead to the inhibition of NK cells through binding to the CD94/NKG2A receptor.…”

Section: Discussionmentioning

confidence: 99%

HLA-E expression in cervical adenocarcinomas: association with improved long-term survival

et al. 2012

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BackgroundCervical cancer is the third most common cancer in women worldwide. The most common histopathological subtype is cervical squamous cell carcinoma (SCC, 75-80%), followed by adenocarcinoma (AC) and adenosquamous carcinoma (ASC; together 15-20%). Rising incidence rates of AC have been observed relative and absolute to SCC and evidence is accumulating that cervical AC is a distinct clinical entity. Cervical SCC, ASC, and AC are caused by a persistent infection with high-risk human papillomavirus (HPV) and failed control of the immune system plays a pivotal role in the carcinogenesis of all three histopathological subtypes. Human leukocyte antigen E (HLA-E), a non-classical HLA class Ib molecule, plays an important role in immune surveillance and immune escape of virally infected cells. In this study we investigated HLA-E expression in three well-defined cohorts of cervical AC, ASC, and SCC patients, and determined whether HLA-E expression was associated with histopathological parameters and patient survival.Methods and resultsHLA-E expression was assessed by immunohistochemistry on formalin-fixed, paraffin-embedded tissue sections of 79 SCC, 38 ASC, and 75 AC patients. All patients included were International Federation of Gynaecology and Obstetrics stage I-II and underwent radical hysterectomy with lymphadenectomy as primary treatment. Significant differences between the histopathological subgroups were detected for age distribution, HPV positivity, HPV type distribution, tumour size, tumour infiltration depth, lymph-vascular space invasion, and adjuvant radiotherapy. High expression of HLA-E was found in 107/192 (56%) cervical carcinomas, with significantly more overexpression in cervical AC compared to SCC and ASC (37/79 SCC, 18/38 ASC, and 52/75 AC; P = 0.010). High HLA-E expression in cervical AC was associated with favourable long term disease-specific and recurrence-free survival (P = 0.005 and P = 0.001, respectively).ConclusionHigh expression of HLA-E occurred in the majority of all histopathological subtypes of cervical cancer; especially in cervical AC. High HLA-E expression in cervical AC was associated with improved patient survival. This study also highlights the importance of careful evaluation of cervical carcinomas to distinguish histopathological subtypes. In the future, insight into the biological behaviour and distinct molecular carcinogenetic processes of the AC, ASC, and SCC subtypes may contribute to the development of more tumour-specific treatment strategies.

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“…Non-classical HLA class I molecules (HLA-E and HLA-G) play a crucial role in immune surveillance by NK cells. Expression of these molecules on the cell surface causes an inhibitory effect on NK-cell attack (Khong and Restifo, 2002; Marin et al , 2003; Wischhusen et al , 2007). Another tumour escape mechanism of immunosurveillance is attraction and induction of immunosuppressive regulatory T cells (Tregs) in the tumour microenvironment (Cerwenka et al , 2001).…”

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confidence: 99%

Immunological subtypes in breast cancer are prognostic for invasive ductal but not for invasive lobular breast carcinoma

et al. 2014

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Background:Classical patient and tumour characteristics are the benchmark of personalised breast cancer (BC) management. Recent evidence has demonstrated that immune and molecular profiling of BC may also play an important role. Despite evidence of differences between invasive ductal (IDC) and lobular (ILC) BC, they are infrequently accounted for when making treatment decisions for individual patients. The purpose of this study was to investigate the relevance of the tumour immune response in the major histological subtypes of BC. We also assessed the relationship between immune responses and molecular subtypes and their prognostic potential.Methods:Immunostains were done for HLA-I, HLA-E, HLA-G, Tregs, NK cells and CTLs for the composition of the immune profiles and Ki67, EGFR, CK5/6, ER, PR and HER2 for molecular profiles in 714 breast cancer patients who underwent primary surgery.Results:No significant association was found between IDC (90.6%) and ILC (9.4%) and tumour immune subtypes (P=0.4) and molecular subtypes (P=0.4). However, for the relapse-free period (RFP) tumour immune subtyping was prognostic (P=0.002) in IDC, but not ILC. Contrary to ILC, IDC patients frequently expressed higher cleaved caspase-3 and Ki67, which was prognostic. Intermediate immune-susceptible IDC expressing high cleaved caspase-3 or Ki67 showed worse RFP than those with low expression (caspase-3: P=0.004; Ki67: P=0.002); this was not seen for ILC or in high or low immune-susceptible tumour types for either IDC or ILC.Conclusions:Tumour immune characteristics and host immune responses are prognostic in IDC, but not ILC. In addition, tumour immune profiles are only prognostic in Luminal A tumours.

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Analysis of HLA-E expression in human tumors

Cited by 150 publications

References 36 publications

Expression of the Classical and Nonclassical HLA Molecules in Breast Cancer

Expression of the Classical and Nonclassical HLA Molecules in Breast Cancer

HLA-E expression in cervical adenocarcinomas: association with improved long-term survival

Immunological subtypes in breast cancer are prognostic for invasive ductal but not for invasive lobular breast carcinoma

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