Gene Summary

Gene:HLA-E; major histocompatibility complex, class I, E
Aliases: QA1, HLA-6.2
Summary:HLA-E belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-E binds a restricted subset of peptides derived from the leader peptides of other class I molecules. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:HLA class I histocompatibility antigen, alpha chain E
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Latest Publications: HLA-E (cancer-related)

Graff-Baker AN, Orozco JIJ, Marzese DM, et al.
Epigenomic and Transcriptomic Characterization of Secondary Breast Cancers.
Ann Surg Oncol. 2018; 25(10):3082-3087 [PubMed] Related Publications
BACKGROUND: Molecular alterations impact tumor prognosis and response to treatment. This study was designed to identify transcriptomic and epigenomic signatures of breast cancer (BC) tumors from patients with any prior malignancy.
METHODS: RNA-sequencing and genome-wide DNA methylation profiles from BCs were generated in the Cancer Genome Atlas project. Patients with secondary breast cancer (SBC) were separated by histological subtype and matched to primary breast cancer controls to create two independent cohorts of invasive ductal (IDC, n = 36) and invasive lobular (ILC, n = 40) carcinoma. Differentially expressed genes, as well as differentially methylated genomic regions, were integrated to identify epigenetically regulated abnormal gene pathways in SBCs.
RESULTS: Differentially expressed genes were identified in IDC SBCs (n = 727) and in ILC SBCs (n = 261; Wilcoxon's test; P < 0.05). In IDC SBCs, 105 genes were upregulated and hypomethylated, including an estrogen receptor gene, and 73 genes were downregulated and hypermethylated, including genes involved in antigen presentation and interferon response pathways (HLA-E, IRF8, and RELA). In ILC SBCs, however, only 17 genes were synchronously hypomethylated and upregulated, whereas 46 genes hypermethylated and downregulated. Interestingly, the SBC gene expression signatures closely corresponded with each histological subtype with only 1.51% of genes overlapping between the two histological subtypes.
CONCLUSIONS: Differential gene expression and DNA methylation signatures are seen in both IDC and ILC SBCs, including genes that are relevant to tumor growth and proliferation. Differences in gene expression signatures corresponding with each histological subtype emphasize the importance of disease subtype-specific evaluations of molecular alterations.

Pan Y, Lu L, Chen J, et al.
Identification of potential crucial genes and construction of microRNA-mRNA negative regulatory networks in osteosarcoma.
Hereditas. 2018; 155:21 [PubMed] Free Access to Full Article Related Publications
Background: This study aimed to identify potential crucial genes and construction of microRNA-mRNA negative regulatory networks in osteosarcoma by comprehensive bioinformatics analysis.
Methods: Data of gene expression profiles (GSE28424) and miRNA expression profiles (GSE28423) were downloaded from GEO database. The differentially expressed genes (DEGs) and miRNAs (DEMIs) were obtained by R Bioconductor packages. Functional and enrichment analyses of selected genes were performed using DAVID database. Protein-protein interaction (PPI) network was constructed by STRING and visualized in Cytoscape. The relationships among the DEGs and module in PPI network were analyzed by plug-in NetworkAnalyzer and MCODE seperately. Through the TargetScan and comparing target genes with DEGs, the miRNA-mRNA regulation network was established.
Results: Totally 346
Conclusion: Our study indicated possible differentially expressed genes and miRNA, and microRNA-mRNA negative regulatory networks in osteosarcoma by bioinformatics analysis, which may provide novel insights for unraveling pathogenesis of osteosarcoma.

Godfrey DI, Le Nours J, Andrews DM, et al.
Unconventional T Cell Targets for Cancer Immunotherapy.
Immunity. 2018; 48(3):453-473 [PubMed] Related Publications
Most studies on the immunotherapeutic potential of T cells have focused on CD8 and CD4 T cells that recognize peptide antigens (Ag) presented by polymorphic major histocompatibility complex (MHC) class I and MHC class II molecules, respectively. However, unconventional T cells, which interact with MHC class Ib and MHC-I like molecules, are also implicated in tumor immunity, although their role therein is unclear. These include unconventional T cells targeting MHC class Ib molecules such as HLA-E and its murine ortholog Qa-1b, natural killer T (NKT) cells, mucosal associated invariant T (MAIT) cells, and γδ T cells. Here, we review the current understanding of the roles of these unconventional T cells in tumor immunity and discuss why further studies into the immunotherapeutic potential of these cells is warranted.

Litjens NHR, van der Wagen L, Kuball J, Kwekkeboom J
Potential Beneficial Effects of Cytomegalovirus Infection after Transplantation.
Front Immunol. 2018; 9:389 [PubMed] Free Access to Full Article Related Publications
Cytomegalovirus (CMV) infection can cause significant complications after transplantation, but recent emerging data suggest that CMV may paradoxically also exert beneficial effects in two specific allogeneic transplant settings. These potential benefits have been underappreciated and are therefore highlighted in this review. First, after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) using T-cell and natural killer (NK) cell-replete grafts, CMV reactivation is associated with protection from leukemic relapse. This association was not observed for other hematologic malignancies. This anti-leukemic effect might be mediated by CMV-driven expansion of donor-derived memory-like NKG2C

Deng H, Zeng J, Zhang T, et al.
Histone H3.3K27M Mobilizes Multiple Cancer/Testis (CT) Antigens in Pediatric Glioma.
Mol Cancer Res. 2018; 16(4):623-633 [PubMed] Related Publications
Lysine to methionine mutations at position 27 (K27M) in the histone H3 (H3.3 and H3.1) are highly prevalent in pediatric high-grade gliomas (HGG) that arise in the midline of the central nervous system. H3K27M perturbs the activity of polycomb repressor complex 2 and correlates with DNA hypomethylation; however, the pathways whereby H3K27M drives the development of pediatric HGG remain poorly understood. To understand the mechanism of pediatric HGG development driven by H3.3K27M and discover potential therapeutic targets or biomarkers, we established pediatric glioma cell model systems harboring H3.3K27M and performed microarray analysis. H3.3K27M caused the upregulation of multiple cancer/testis (CT) antigens, such as ADAMTS1, ADAM23, SPANXA1, SPANXB1/2, IL13RA2, VCY, and VCX3A, in pediatric glioma cells. Chromatin immunoprecipitation analysis from H3.3K27M cells revealed decreased H3K27me3 levels and increased H3K4me3 levels on the

Vangangelt KMH, van Pelt GW, Engels CC, et al.
Prognostic value of tumor-stroma ratio combined with the immune status of tumors in invasive breast carcinoma.
Breast Cancer Res Treat. 2018; 168(3):601-612 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Complex interactions occur between cancer cells and cells in the tumor microenvironment. In this study, the prognostic value of the interplay between tumor-stroma ratio (TSR) and the immune status of tumors in breast cancer patients was evaluated.
METHODS: A cohort of 574 breast cancer patients was analyzed. The percentage of tumor stroma was visually estimated on Hematoxylin and Eosin (H&E) stained histological tumor tissue sections. Immunohistochemical staining was performed for classical human leukocyte antigen (HLA) class I, HLA-E, HLA-G, markers for regulatory T (Treg) cells, natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs).
RESULTS: TSR (P < .001) and immune status of tumors (P < .001) were both statistically significant for recurrence free period (RFP) and both independent prognosticators (P < .001) in which tumors with a high stromal content behave more aggressively as well as tumors with a low immune status. Ten years RFP for patients with a stroma-low tumor and high immune status profile was 87% compared to 17% of patients with a stroma-high tumor combined with low immune status profile (P < .001). Classical HLA class I is the most prominent immune marker in the immune status profiles.
CONCLUSIONS: Determination of TSR is a simple, fast and cheap method. The effect on RFP of TSR when combined with immune status of tumors or expression of classical HLA class I is even stronger. Both are promising for further prediction and achievement of tailored treatment for breast cancer patients.

Hakam MS, Miranda-Sayago JM, Hayrabedyan S, et al.
Preimplantation Factor (PIF) Promotes HLA-G, -E, -F, -C Expression in JEG-3 Choriocarcinoma Cells and Endogenous Progesterone Activity.
Cell Physiol Biochem. 2017; 43(6):2277-2296 [PubMed] Related Publications
BACKGROUND/AIMS: Pregnancy success requires mandatory maternal tolerance of the semi/ allogeneic embryo involving embryo-derived signals. Expression levels of PreImplantation Factor (PIF), a novel peptide secreted by viable embryos, correlate with embryo development, and its early detection in circulation correlates with a favourable pregnancy outcome. PIF enhances endometrial receptivity to promote embryo implantation. Via the p53 pathway, it increases trophoblast invasion, improving cell survival / immune privilege. PIF also reduces spontaneous and LPS-induced foetal death in immune naïve murine model. We examined PIF effect on gene expression of human leukocyte antigen (HLA-G, -E -F and -C) and the influence of PIF on local progesterone activity in JEG-3 choriocarcinoma cells.
METHODS: PIF and progesterone (P4) effects on JEG-3 cells surface and intracellular HLA molecules was tested using monoclonal antibodies, flow cytometry, and Western blotting. PIF and IL17 effects on P4 and cytokines secretion was determined by ELISA. PIF and P4 effects on JEG-3 cells proteome was examined using 2D gel staining followed by spot analysis, mass spectrometry and bioinformatic analysis.
RESULTS: In cytotrophoblastic JEG-3 cells PIF increased intracellular expression of HLA-G, HLA-F, HLA-E and HLA-C and surface expression of HLA-G, HLA-E and HLA-C in dose and time dependent manner. In case of HLA-E, -F results were confirmed also by Western blot. Proteome analysis confirmed an increase in HLA-G, pro-tolerance FOXP3+ regulatory T cells (Tregs), coagulation factors and complement regulator. In contrast, PIF reduced PRDX2 and HSP70s to negate oxidative stress and protein misfolding. PIF enhanced local progesterone activity, increasing steroid secretion and the receptor protein. It also promoted the secretion of the Th1/Th2 cytokines (IL-10, IL-1β, IL-8, GM-CSF and TGF-β1), resulting in improved maternal signalling.
CONCLUSION: PIF can generate a pro-tolerance milieu by enhancing the expression of HLA molecules and by amplifying endogenous progesterone activity. A Fast-Track clinical trial for autoimmune disease has been satisfactorily completed. The acquired data warrants PIF use for the treatment of early pregnancy disorders.

Gonçalves AS, Mosconi C, Jaeger F, et al.
Overexpression of immunomodulatory mediators in oral precancerous lesions.
Hum Immunol. 2017; 78(11-12):752-757 [PubMed] Related Publications
Human leukocyte antigen (HLA) G and E, programmed cell death 1 ligand 1 (PD-L1), IL-10 and TGF-β are proteins involved in failure of the antitumor immune response. We investigated the expression of these immunomodulatory mediators in oral precancerous lesions (oral leukoplakia-OL; n=80) and whether these molecules were related to the risk of malignant transformation. Samples of normal mucosa (n=20) and oral squamous cells carcinoma (OSCC, n=20) were included as controls. Tissue and saliva samples were analyzed by immunohistochemistry and ELISA respectively. Fifteen OL samples showed severe dysplasia (18.7%) and 40 samples (50%) presented combined high Ki-67/p53. Irrespective of the degree of epithelial dysplasia and the proliferation/apoptosis index of OL, the expression of HLA-G, -E, PD-L1, IL-10, TGF-β2 and -β3 was higher to control (P<0.05) and similar to OSCC (P>0.05). The number of granzyme B

Tsamadou C, Fürst D, Vucinic V, et al.
Human leukocyte antigen-E mismatch is associated with better hematopoietic stem cell transplantation outcome in acute leukemia patients.
Haematologica. 2017; 102(11):1947-1955 [PubMed] Free Access to Full Article Related Publications
The immunomodulatory role of human leukocyte antigen (HLA)-E in hematopoietic stem cell transplantation (HSCT) has not been extensively investigated. To this end, we genotyped 509 10/10 HLA unrelated transplant pairs for

Melsted WN, Johansen LL, Lock-Andersen J, et al.
HLA class Ia and Ib molecules and FOXP3+ TILs in relation to the prognosis of malignant melanoma patients.
Clin Immunol. 2017; 183:191-197 [PubMed] Related Publications
HLA class Ia (HLA-ABC) and HLA class Ib (HLA-E, -F and -G) molecules and FOXP3+ tumor-infiltrating lymphocytes (TILs) are often reported as relevant factors of tumor immune regulation. We investigated their expression as prognostic factors in 200 patients with primary cutaneous melanoma (PCM). In our cohort, patients with tumors showing upregulation of HLA-ABC molecules had significantly thicker tumors (32% vs 7%, P<0.001), frequent ulceration (20% vs 6%, P=0.007) and frequent nodular melanomas (20% vs 4%, P=0.001). Additionally, high expression of HLA-G in the tumor was a sign of bad prognosis for the patients, being associated with thick tumors (30% vs 12%, P=0.017), ulceration (24% vs 5%, P<0.001) and positive sentinel node (13% vs 6%, P=0.015). HLA-E, HLA-F and FOXP3+ TILs were not indicative of the prognosis in PCM. High HLA-ABC and HLA-G were associated with tumor aggressiveness and could be relevant predictive markers for effective immunotherapy of melanoma tumors.

Cicchini L, Blumhagen RZ, Westrich JA, et al.
High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human Keratinocytes.
Sci Rep. 2017; 7(1):3633 [PubMed] Free Access to Full Article Related Publications
Human papillomavirus (HPV) infection distinctly alters methylation patterns in HPV-associated cancer. We have recently reported that HPV E7-dependent promoter hypermethylation leads to downregulation of the chemokine CXCL14 and suppression of antitumor immune responses. To investigate the extent of gene expression dysregulated by HPV E7-induced DNA methylation, we analyzed parallel global gene expression and DNA methylation using normal immortalized keratinocyte lines, NIKS, NIKS-16, NIKS-18, and NIKS-16∆E7. We show that expression of the MHC class I genes is downregulated in HPV-positive keratinocytes in an E7-dependent manner. Methylome analysis revealed hypermethylation at a distal CpG island (CGI) near the HLA-E gene in NIKS-16 cells compared to either NIKS cells or NIKS-16∆E7 cells, which lack E7 expression. The HLA-E CGI functions as an active promoter element which is dramatically repressed by DNA methylation. HLA-E protein expression on cell surface is downregulated by high-risk HPV16 and HPV18 E7 expression, but not by low-risk HPV6 and HPV11 E7 expression. Conversely, demethylation at the HLA-E CGI restores HLA-E protein expression in HPV-positive keratinocytes. Because HLA-E plays an important role in antiviral immunity by regulating natural killer and CD8

Frazao A, Colombo M, Fourmentraux-Neves E, et al.
Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on
Cancer Immunol Res. 2017; 5(7):582-593 [PubMed] Related Publications
Over 60% of human melanoma tumors bear a mutation in the

Wang SX, Xu YP, He LM
A novel HLA-E allele, HLA-E*01:01:01:07, identified in a Chinese leukemia patient.
HLA. 2017; 89(5):327-330 [PubMed] Related Publications
A novel HLA-E allele, HLA-E*01:01:01:07, was identified in a Chinese leukemia patient.

Xu YP, Wang SX, Hong WX
A novel HLA-E allele, HLA-E*01:01:01:06, identified in a Chinese Leukemia patient.
HLA. 2017; 89(4):260-262 [PubMed] Related Publications
A novel HLA-E allele, HLA-E*01:01:01:06, was identified in a Chinese leukemia patient.

Ferns DM, Heeren AM, Samuels S, et al.
Classical and non-classical HLA class I aberrations in primary cervical squamous- and adenocarcinomas and paired lymph node metastases.
J Immunother Cancer. 2016; 4:78 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tumors avoid destruction by cytotoxic T cells (CTL) and natural killer (NK) cells by downregulation of classical human leukocyte antigens (HLA) and overexpression of non-classical HLA. This is the first study to investigate HLA expression in relation to histology (squamous cell carcinoma (SCC) vs. adenocarcinoma (AC)), clinicopathological parameters and survival in a large cervical cancer patient cohort.
METHODS: Classical (HLA-A and HLA-B/C)- and non-classical HLA molecules (HLA-E and HLA-G) were studied on primary tumors and paired lymph node (LN) metastases from cervical cancer patients (
RESULTS: Decreased expression of HLA-A (SCC
CONCLUSION: These results strengthen the idea of tumor immune escape variants leading to metastasis. Moreover, SCC tumors showing downregulation of HLA-A or total classical HLA in combination with HLA-G expression had poor prognosis. Our findings warrant further analysis of HLA expression as a biomarker for patient selection for CTL- and NK- cell based immunotherapeutic intervention.

Wagner B, da Silva Nardi F, Schramm S, et al.
HLA-E allelic genotype correlates with HLA-E plasma levels and predicts early progression in chronic lymphocytic leukemia.
Cancer. 2017; 123(5):814-823 [PubMed] Related Publications
BACKGROUND: Human leukocyte antigen-E (HLA-E) is a nonclassical major histocompatibility complex class I molecule that recently came into sharper focus as a putative marker of advanced tumor stages and disease progression. In solid tumors, increased HLA-E expression as well as elevated soluble HLA-E (sHLA-E) plasma levels are associated with a poor prognosis; however, a role for HLA-E in hematologic malignancies remains to be established.
METHODS: The authors analyzed HLA-E alleles and sHLA-E levels in a cohort of 110 individuals with chronic lymphocytic leukemia (CLL).
RESULTS: In patients with CLL, levels of sHLA-E increased with advanced disease stage (P = .01) and decreased after therapy (P = .01). Longitudinal follow-up revealed that both HLA-E*01:03 alleles and high levels of sHLA-E were significantly associated with a requirement for early treatment in patients with CLL (P = .027 and P = .023, respectively). In vitro, sHLA-E inhibited degranulation and interferon-γ production by natural killer (NK) cells when cocultivated with tumor cells. Moreover, sHLA-E loaded onto microspheres induced transforming growth factor-β release by NK cells. Multivariate analysis revealed that the presence of at least 1 HLA-E*01:03 allele was an independent predictor of a requirement for early treatment.
CONCLUSIONS: HLA-E alleles and sHLA-E levels may represent novel biomarkers for early disease progression in patients with CLL. Cancer 2017;123:814-23. © 2016 American Cancer Society.

Özgül Özdemir RB, Özdemir AT, Oltulu F, et al.
A comparison of cancer stem cell markers and nonclassical major histocompatibility complex antigens in colorectal tumor and noncancerous tissues.
Ann Diagn Pathol. 2016; 25:60-63 [PubMed] Related Publications
Colorectal carcinoma (CRC) is one of the most fatal types of cancer in both women and men, and, unfortunately, patients are often diagnosed at an advanced stage. Cancer stem cells (CSCs) are associated with poor prognosis, metastasis, and recurrence, as well as chemotherapy and radiotherapy resistance. Therefore, different treatment alternatives are needed to facilitate the elimination of CSCs. One such approach is immunotherapy; however, tumor cells can evade immune cells by alteration of the expression patterns of human leukocyte antigens (HLA). In this study, we immunohistochemically investigated the expression patterns of CSC-specific markers CD44, CD133, Nanog, and Oct3/4, and immunosuppressive molecules HLA-G and -E in advanced CRC tumor tissues and noncancerous colon biopsies. We found significantly increased CD44, Nanog, Oct3/4, HLA-G, and HLA-E expression in the CRC tumor tissues compared with the noncancerous colon biopsies. These findings suggest that some tumor cells may be CSC-like and that the increased expression of HLA-G and HLA-E may be considered as an immune-evasive adaptation. Therefore, the nonclassical major histocompatibility complex class Ib antigens HLA-G and HLA-E may be potential targets in the elimination of CRC-CSCs. However, more detailed studies are required to support our findings.

Zheng D, Wang X, Xu RH
Concise Review: One Stone for Multiple Birds: Generating Universally Compatible Human Embryonic Stem Cells.
Stem Cells. 2016; 34(9):2269-75 [PubMed] Related Publications
With ongoing clinical trials, human embryonic stem cells (hESCs) have shown substantial potential for regenerative medicine. However, due to the mismatch of human leukocyte antigens (HLAs) between hESC-derived allografts and recipients, immunosuppressant regimens must be used to prevent immune rejection of the grafts. Considerable efforts have been devoted to overcoming this hurdle via the derivation and banking of human nuclear transfer ESCs, parthenogenetic ESCs, and induced pluripotent stem cells. However, ethical and safety concerns remain, hindering the application of these types of pluripotent cells. Other approaches have recently been explored to generate universally compatible hESCs through the silencing or deletion of HLAs or genes essential for HLA expression, including β-2-microglobulin and class-II MHC transactivator, as well as the induction of immunosuppression via the ectopic expression of non-classical HLAs (e.g., HLA-E and -G), cytotoxic T lymphocyte antigen 4 fused with immunoglobulin, and programmed death ligand-1. In this review, we introduce developments in this line of research and discuss strategies to reduce the tumorigenic concerns regarding hESCs, especially after they acquire the capability to escape immune surveillance. Stem Cells 2016;34:2269-2275.

Gallegos CE, Michelin S, Dubner D, Carosella ED
Immunomodulation of classical and non-classical HLA molecules by ionizing radiation.
Cell Immunol. 2016; 303:16-23 [PubMed] Related Publications
Radiotherapy has been employed for the treatment of oncological patients for nearly a century, and together with surgery and chemotherapy, radiation oncology constitutes one of the three pillars of cancer therapy. Ionizing radiation has complex effects on neoplastic cells and on tumor microenvironment: beyond its action as a direct cytotoxic agent, tumor irradiation triggers a series of alterations in tumoral cells, which includes the de novo synthesis of particular proteins and the up/down-regulation of cell surface molecules. Additionally, ionizing radiation may induce the release of "danger signals" which may, in turn lead to cellular and molecular responses by the immune system. This immunomodulatory action of ionizing radiation highlights the importance of the combined use (radiotherapy plus immunotherapy) for cancer healing. Major histocompatibility complex antigens (also called Human Leukocyte Antigens, HLA in humans) are one of those molecules whose expression is modulated after irradiation. This review summarizes the modulatory properties of ionizing radiation on the expression of HLA class I (classical and non-classical) and class II molecules, with special emphasis in non-classical HLA-I molecules.

Douik H, Romdhane NA, Guemira F
Are HLA-E*0103 alleles predictive markers for nasopharyngeal cancer risk?
Pathol Res Pract. 2016; 212(4):345-9 [PubMed] Related Publications
BACKGROUND: Nasopharyngeal carcinoma (NPC) is a particular entity of head neck cancer, tightly related to Epstein-Barr virus infection and thus to HLA genes. In this study, we aimed to analyze HLA-E polymorphism in NPC advent and prognosis. 130 unrelated patients with CNP and 180 unrelated and healthy controls were included in our study. HLA-E genotyping was performed by PCR/RFLP method; SPSS (13.0) was used for statistical analysis, and survival curbs were established with the "Kaplan-Meier" method (Log Rank<0.05).
RESULTS: We found a significant difference within HLA-E*103 variants between patients and controls: E*1031 and E*1032 were associated with CNP (OR=1.613, p=0.013 and OR=1.0809, p=0.055), and E*1033 with controls (OR=0.254, p<10(-4)).
CONCLUSION: Our study reveals that HLA-E polymorphism is associated with nasopharyngeal cancer. HLA-E expression studies could be used to understand the implication of E*103 variants.

Muccio L, Bertaina A, Falco M, et al.
Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing αβ+T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies.
Haematologica. 2016; 101(3):371-81 [PubMed] Free Access to Full Article Related Publications
We analyzed the impact of human cytomegalovirus infection on the development of natural killer cells in 27 pediatric patients affected by hematological malignancies, who had received a HLA-haploidentical hematopoietic stem cell transplantation, depleted of both α/β+ T cells and B cells. In line with previous studies in adult recipients of umbilical cord blood transplantation, we found that human cytomegalovirus reactivation accelerated the emergence of mature natural killer cells. Thus, most children displayed a progressive expansion of a memory-like natural killer cell subset expressing NKG2C, a putative receptor for human cytomegalovirus, and CD57, a marker of terminal natural killer cell differentiation. NKG2C(+)CD57(+) natural killer cells were detectable by month 3 following hematopoietic stem cell transplantation and expanded until at least month 12. These cells were characterized by high killer Ig-like receptors (KIRs) and leukocyte inhibitory receptor 1 (LIR-1) and low Siglec-7, NKG2A and Interleukin-18Rα expression, killed tumor targets and responded to cells expressing HLA-E (a NKG2C ligand). In addition, they were poor Interferon-γ producers in response to Interleukin-12 and Interleukin-18. The impaired response to these cytokines, together with their highly differentiated profile, may reflect their skewing toward an adaptive condition specialized in controlling human cytomegalovirus. In conclusion, in pediatric patients receiving a type of allograft different from umbilical cord blood transplantation, human cytomegalovirus also induced memory-like natural killer cells, possibly contributing to controlling infections and reinforcing anti-leukemia effects.

Wolpert F, Happold C, Reifenberger G, et al.
Interferon-β Modulates the Innate Immune Response against Glioblastoma Initiating Cells.
PLoS One. 2015; 10(10):e0139603 [PubMed] Free Access to Full Article Related Publications
Immunotherapy targeting glioblastoma initiating cells (GIC) is considered a promising strategy. However, GIC are prone to evade immune response and there is a need for potent adjuvants. IFN-β might enhance the immune response and here we define its net effect on the innate immunogenicity of GIC. The transcriptomes of GIC treated with IFN-β and controls were assessed by microarray-based expression profiling for altered expression of immune regulatory genes. Several genes involved in adaptive and innate immune responses were regulated by IFN-β. We validated these results using reverse transcription (RT)-PCR and flow cytometry for corresponding protein levels. The up-regulation of the NK cell inhibitory molecules HLA-E and MHC class I was balanced by immune stimulating effects including the up-regulation of nectin-2. In 3 out of 5 GIC lines tested we found a net immune stimulating effect of IFN-β in cytotoxicity assays using NKL cells as effectors. IFN-β therefore warrants further investigation as an adjuvant for immunotherapy targeting GIC.

Martín P, Krsnik I, Navarro B, et al.
HLA Allele E*01:01 Is Associated with a Reduced Risk of EBV-Related Classical Hodgkin Lymphoma Independently of HLA-A*01/*02.
PLoS One. 2015; 10(8):e0135512 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: An inefficient immune response against Epstein-Barr virus (EBV) infection is related to the pathogenesis of a subgroup of classical Hodgkin lymphomas (cHL). Some EBV immune-evasion mechanisms target HLA presentation, including the non-classical HLA-E molecule. HLA-E can be recognized by T cells via the TCR, and it also regulates natural killer (NK) cell signaling through the inhibitory CD94/NKG2A receptor. Some evidences indicate that EBV-infected B-cells promote the proliferation of NK subsets bearing CD94/NKG2A, suggesting a relevant function of these cells in EBV control. Variations in CD94/NKG2A-HLA-E interactions could affect NK cell-mediated immunity and, consequently, play a role in EBV-driven transformation and lymphomagenesis. The two most common HLA-E alleles, E*01:01 and E*01:03, differ by a single amino acid change that modifies the molecule function. We hypothesized that the functional differences in these variants might participate in the pathogenicity of EBV.
AIM: We studied two series of cHL patients, both with EBV-positive and-negative cases, and a cohort of unrelated controls, to assess the impact of HLA-E variants on EBV-related cHL susceptibility.
RESULTS: We found that the genotypes with at least one copy of E*01:01 (i.e., E*01:01 homozygous and heterozygous) were underrepresented among cHL patients from both series compared to controls (72.6% and 71.6% vs 83%, p = 0.001). After stratification by EBV status, we found low rates of E*01:01-carriers mainly among EBV-positive cases (67.6%). These reduced frequencies are seen independently of other factors such as age, gender, HLA-A*01 and HLA-A*02, HLA alleles positively and negatively associated with the disease (adjusted OR = 0.4, p = 0.001). Furthermore, alleles from both HLA loci exert a cumulative effect on EBV-associated cHL susceptibility.
CONCLUSIONS: These results indicate that E*01:01 is a novel protective genetic factor in EBV-associated cHL and support a role for HLA-E recognition on the control of EBV infection and lymphomagenesis.

Schlegel P, Ditthard K, Lang P, et al.
NKG2D Signaling Leads to NK Cell Mediated Lysis of Childhood AML.
J Immunol Res. 2015; 2015:473175 [PubMed] Free Access to Full Article Related Publications
Natural killer cells have been shown to be relevant in the recognition and lysis of acute myeloid leukemia. In childhood acute lymphoblastic leukemia, it was shown that HLA I expression and KIR receptor-ligand mismatch significantly impact ALL cytolysis. We characterized 14 different primary childhood AML blasts by flow cytometry including NKG2D ligands. Further HLA I typing of blasts was performed and HLA I on the AML blasts was quantified. In two healthy volunteer NK cell donors HLA I typing and KIR genotyping were done. Blasts with high NKG2D ligand expression had significantly higher lysis by isolated NK cells. Grouping the blasts by NKG2D ligand expression led to a significant inverse correlation of HLA I expression and cytolysis in NKG2D low blasts. Furthermore, a significant positive correlation of NKG2D ligand expression and blast cytolysis was shown. No impact of KIR ligand-ligand mismatch was found but a significantly increased lysis of homozygous C2 blasts by KIR2DL1 negative NK cells (donor B) was revealed. In conclusion, NKG2D signaling leads to NK cell mediated lysis of childhood AML despite high HLA I expression.

Ravindranath MH, Terasaki PI, Pham T, Jucaud V
The Monospecificity of Novel Anti-HLA-E Monoclonal Antibodies Enables Reliable Immunodiagnosis, Immunomodulation of HLA-E, and Upregulation of CD8+ T Lymphocytes.
Monoclon Antib Immunodiagn Immunother. 2015; 34(3):135-53 [PubMed] Related Publications
In human cancers, over-expression of HLA-E is marked by gene expression. However, immunolocalization of HLA-E on tumor cells is impeded by the HLA-Ia reactivity of commercial anti-HLA-E monoclonal antibodies (MAbs). So there was a clear need to develop monospecific anti-HLA-E MAbs for reliable immunodiagnosis of HLA-E, particularly considering the prognostic relevance of HLA-E in human cancer. HLA-E overexpression is correlated with disease progression and poor survival of patients, both of which are attributed to the suppression of anti-tumor activity of cytotoxic T cells mediated by HLA-E. The suppression mechanism involves the binding of HLA-E-specific amino acids located on the α1 and α2 helices of HLA-E to the inhibitory receptors (CD94/NKG2a) on CD8+ T lymphocytes. An anti-HLA-E MAb that recognizes these HLA-E-specific sequences can not only be a monospecific MAb with potential for specific immunolocalization of HLA-E but can also block the sequences from interacting with the CD94/NKG2a receptors. We therefore developed several clones that secrete such HLA-E-specific MAbs; then we assessed the ability of the MAbs to bind to the amino acid sequences interacting with the CD94/NKG2a receptors by inhibiting them from binding to HLA-E with peptides that inhibit receptor binding. Elucidation of the immunomodulatory capabilities of these monospecific MAbs showed that they can induce proliferation of CD8+ T cells with or without co-stimulation. These novel MAbs can serve a dual role in combating cancer by blocking interaction of HLA-E with CD94/NKG2a and by promoting proliferation of both non-activated and activated CD8+ cytotoxic αβ T cells.

Ishigami S, Arigami T, Okumura H, et al.
Human leukocyte antigen (HLA)-E and HLA-F expression in gastric cancer.
Anticancer Res. 2015; 35(4):2279-85 [PubMed] Related Publications
Human leukocyte antigen (HLA)-E and HLA-F are classified as non-classical HLA class Ib antigens. Ectopic HLA-E and HLA-F expression was recently detected in cancer cells; however, the clinical implication of their expression remains unknown. A total of 209 patients with gastric cancer were enrolled in this study. Immunohistochemistry was used to evaluate the expression of HLA-E and HLA-F in gastric cancer specimens. HLA-E and HLA-F expression were seen in the cell membrane. HLA-E and HLA-F expression significantly correlated with depth of invasion, nodal involvement, lymphatic invasion, and venous invasion. No significant correlation between HLA-E and HLA-F expression was found (p<0.05, r=0.24). The five-year survival rate of the HLA-E-positive group and HLA-F-positive group were significantly poorer than that of their respective negative groups. Combination of HLA-E and HLA-F made the p-value smaller than single analysis (p<0.009). This is the first report detailing a clinical implication of HLA-E and HLA-F expression simultaneously in gastric cancer. We identified that the HLA-E and HLA-F in gastric cancer independently affected clinical factors, including postoperative outcome. For HLA-E- or HLA-F-positive gastric cancer, we should settle on a treatment strategy that reinforces the host immune response.

Zheng H, Lu R, Xie S, et al.
Human leukocyte antigen-E alleles and expression in patients with serous ovarian cancer.
Cancer Sci. 2015; 106(5):522-8 [PubMed] Free Access to Full Article Related Publications
Human leukocyte antigen-E (HLA-E) is one of the most extensively studied non-classical MHC class I molecules that is almost non-polymorphic. Only two alleles (HLA-E*0101 and HLA-E*0103) are found in worldwide populations, and suggested to be functional differences between these variants. The HLA-E molecule can contribute to the escape of cancer cells from host immune surveillance. However, it is still unknown whether HLA-E gene polymorphisms might play a role in cancer immune escape. To explore the association between HLA-E alleles and the susceptibility to serous ovarian cancer (SOC), 85 primary SOC patients and 100 healthy women were enrolled. Here, we indicated that high frequency of HLA-E*0103 allele existed in SOC patients by the allele-specific quantitative real-time PCR method. The levels of HLA-E protein expression in SOC patients with the HLA-E*0103 allele were higher than those with the HLA-E*0101 allele using immunohistochemistry analysis. The cell surface expression and functional differences between the two alleles were verified by K562 cells transfected with HLA-E*0101 or HLA-E*0103 allelic heavy chains. The HLA-E*0103 allele made the transfer of the HLA-E molecule to the cell surface easier, and HLA-E/peptides complex more stable. These differences ultimately influenced the function of natural killer cells, showing that the cells transfected with HLA-E*0103 allele inhibited natural killer cells to lysis. This study reveals a novel mechanism regarding the susceptibility to SOC, which is correlated with the HLA-E*0103 allele.

Li L, Tian W, Wang W, et al.
NKG2C copy number variations in five distinct populations in mainland China and susceptibility to nasopharyngeal carcinoma (NPC).
Hum Immunol. 2015; 76(2-3):90-4 [PubMed] Related Publications
In this study, copy number variation (CNV) of NKG2C gene was investigated in 1129 normal, unrelated individuals representing two southern Chinese Han populations (Hunan Han and Guangdong Han), two northern Chinese populations (Inner Mongolia Han and Inner Mongolia Mongol) and one southeastern Chinese Han population (Fujian Han) using polymerase chain reaction-sequence-specific priming (PCR-SSP) method. CNV of NKG2C gene did not vary significantly among the five Chinese populations, with NKG2C gene deletion showing a frequency ranging from 0.2031 to 0.2688. Compared with worldwide ethnic groups, very significant difference was observed between the five Chinese populations and the Mexican mestizos (all Pcorrected=0.0025), and between the Fujian Han population and the German population (Pcorrected=0.005). We further examined CNV of NKG2C and HLA-E allelic distribution in 653 patients afflicted with nasopharyngeal carcinoma (NPC) in Hunan province. Neither CNV of NKG2C nor HLA-E was associated with NPC. There was a trend of reduced NPC risk in individuals who were homozygous for both HLA-E(∗)01:03 and NKG2C deletion (0.46% vs. 2.51%, P=0.0076, Pcorrected=0.0684, OR (95% CI)=0.1794 (0.0473-0.6809)). Taken together, our results suggest that NKG2C deletion and HLA-E signalling pathway does not play a major role in determining genetic susceptibility to NPC.

Mossallam GI, Fattah RA, El-Haddad A, Mahmoud HK
HLA-E polymorphism and clinical outcome after allogeneic hematopoietic stem cell transplantation in Egyptian patients.
Hum Immunol. 2015; 76(2-3):161-5 [PubMed] Related Publications
UNLABELLED: Human leukocyte antigen-E (HLA)-E in a non-classical major histocompatibility complex (MHC) class I (Ib) molecule. HLA-E-peptide complex acts as a ligand for natural killer (NK) cells and CD8+ T lymphocytes playing a dual role in natural and acquired immune responses. The difference in expression levels between HLA-E alleles was suggested to have impact on transplantation outcome. The aim of the study is to evaluate the clinical effect of HLA-E alleles on transplantation in a group of Egyptian patients. HLA-E genotyping was analyzed in eighty-eight recipients of stem cell transplantation using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). HLA-E*01:03 allele showed a trend towards lower cumulative incidence of relapse at 2 years compared to homozygous HLA-E*01:01 genotype (8% versus 21.5%, p=0.09, HR: 0.30, 95% CI: 0.91-1.69). HLA-E was the only factor showing near significant association with relapse incidence. HLA-E polymorphism did not affect the cumulative incidence of acute GVHD grades II-IV at 100 days, the 2-year cumulative incidence of extensive chronic GVHD, transplant related mortality (TRM) or overall survival (OS).
CONCLUSION: the suggested association of HLA-E polymorphism with reduced risk of relapse needs verification in a larger cohort. However, its proposed role in GVL helps better understanding of alloreactivity of T cells and NK cells and their implication in immunotherapy post allogeneic hematopoietic stem cell transplantation.

Djajadiningrat RS, Horenblas S, Heideman DA, et al.
Classic and nonclassic HLA class I expression in penile cancer and relation to HPV status and clinical outcome.
J Urol. 2015; 193(4):1245-51 [PubMed] Related Publications
PURPOSE: Loss of expression of HLA class I is a mechanism of immune evasion in various cancers that is often associated with a worse patient outcome. We analyzed HLA expression in a large cohort with penile cancer in relation to clinical outcome.
MATERIALS AND METHODS: We used penile cancer tissue blocks from 168 patients who underwent surgical resection between 2000 and 2009 to construct tissue microarrays. Immunohistochemical staining was done with antibodies directed against classic and nonclassic HLA molecules. HLA expression was scored semiquantitatively, divided into 3 expression groups and correlated with clinicopathological variables, including HPV and survival. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards models.
RESULTS: Complete and partial loss of total classic HLA class I was observed in 32% and 50% of cases, and up-regulation of HLA-E and G in 16% and 13%, respectively. When corrected for relevant clinical parameters, partial HLA-A loss was significantly associated with decreased survival overall (HR 2.3, 95% CI 1.1-4.6) and in HPV negative patients alone (HR 3.4, 95% CI 1.4-8.4). Abnormal HLA-B/C, E or G expression levels were not associated with survival.
CONCLUSIONS: To our knowledge this is the first study to describe a link between HLA expression and the clinical outcome of penile cancer. HLA down-regulation occurs frequently and partial loss of HLA-A is an independent predictor of poor survival in HPV negative patients. Complete understanding of the mechanisms and relevance of HLA down-regulation and immune evasion in regard to the clinical outcome will contribute to the future design of immunotherapy interventions.

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