Gene Summary

Gene:HLA-G; major histocompatibility complex, class I, G
Aliases: MHC-G
Summary:HLA-G 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-G is expressed on fetal derived placental cells. 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 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:HLA class I histocompatibility antigen, alpha chain G
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (27)
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

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Bladder Cancer
  • Vaginal Cancer
  • Thyroid Cancer
  • Republic of Korea
  • HLA Antigens
  • Gene Expression
  • T-Lymphocytes
  • HLA-G Antigens
  • Stomach Cancer
  • Smoking
  • Breast Cancer
  • Transcription
  • Case-Control Studies
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • Cancer Gene Expression Regulation
  • Transcriptional Activation
  • Messenger RNA
  • Staging
  • Polymorphism
  • Chromosome 6
  • Risk Factors
  • Tobacco Use
  • Genetic Predisposition
  • Tissue Array Analysis
  • Thyroiditis, Autoimmune
  • Flow Cytometry
  • Tumor Burden
  • Major Histocompatibility Complex
  • Reproduction
  • Young Adult
  • Histocompatibility Antigens Class I
  • Genotype
  • 3' Untranslated Regions
  • ROC Curve
  • Biomarkers, Tumor
  • B-Cell Lymphoma
  • Cervical Cancer
  • Reed-Sternberg Cells
  • Tumor Escape
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HLA-G (cancer-related)

Ullah M, Azazzen D, Kaci R, et al.
High Expression of HLA-G in Ovarian Carcinomatosis: The Role of Interleukin-1β.
Neoplasia. 2019; 21(3):331-342 [PubMed] Free Access to Full Article Related Publications
The present study focuses on the influence of the tumor microenvironment on the expression of HLA-G in ovarian cancer and its impact on immune cells. We used carcinomatosis fluids (n = 16) collected from patients diagnosed with epithelial ovarian cancer, detected by an increase in CA125 levels. Our results indicate that HLA-G is expressed by 1) ascitic cell clusters, 2) stromal cells (hospicells) extracted from cancer cell clusters, and 3) cancer cell lines and tumor cells. The origin of HLA-G was linked to inflammatory cytokines present in the cancer microenvironment. In parallel, the ascitic fluid of patients with ovarian cancer contains soluble HLA-G (sHLA-G). The mesothelial cell layer and submesothelial tissues, as well as the immune cell infiltrate, do not secrete HLA-G. In contrast, sHLA-G is absorbed by peritoneal tissues along with mesothelial layers as well as immune cell infiltrates. We demonstrated that interleukin-1β along with TGF-β can be a major HLA-G-inducing factor that upregulates HLA-G expression through the NF-κB pathway. The level of HLA-G in ascites correlated positively with the expression of T regulatory (T-regs) cells, while it negatively correlated with the expression of natural killer and memory cells in tumor-infiltrating immune cells. In conclusion, the production of HLA-G is associated with the presence of inflammatory cytokines and is strongly correlated with microenvironment tolerant cells such as T-regs and diminution of NK and memory T cells.

Li X, Wei X, Xu H, et al.
Expression of leukocyte immunoglobulin-like receptor B2 in hepatocellular carcinoma and its clinical significance.
J Cancer Res Ther. 2018; 14(7):1655-1659 [PubMed] Related Publications
Background: Leukocyte immunoglobulin-like receptor B2 (LILRB2) has recently been considered a promising tumor promoter in human cancers.
Materials and Methods: In this study, the expression of LILRB2 was assessed in 82 samples of surgically resected human hepatocellular carcinoma (HCC) tissues using immunohistochemistry (IHC).
Results: LILRB2 was overexpressed in HCC tissues and its expression was positively and significantly correlated with poor prognostic features of HCC patients, including poor cell differentiation, larger primary tumor size, and shorter overall survival. In addition, there was a positive correlation between the expression of LILRB2 and its classical ligand human leukocyte antigen G in human HCC tissues.
Conclusion: LILRB2 might play an important role in HCC progression and correlate with poor prognosis of HCC.

Lu Y, Kweon SS, Tanikawa C, et al.
Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer.
Gastroenterology. 2019; 156(5):1455-1466 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND & AIMS: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations.
METHODS: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels.
RESULTS: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10
CONCLUSIONS: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.

Na KJ, Choi H
Immune landscape of papillary thyroid cancer and immunotherapeutic implications.
Endocr Relat Cancer. 2018; 25(5):523-531 [PubMed] Related Publications
Although papillary thyroid cancer (PTC) is curable with excellent survival rate, patients with dedifferentiated PTC suffer the recurrence or death. As cancer immune escape plays a critical role in cancer progression, we aimed to investigate the relationship between differentiation and immune landscape of PTC and its implications for immunotherapy. Using The Cancer Genome Atlas data, we estimated the immune cell enrichment scores and overall immune infiltration, ImmuneScore, to characterize the immune landscape of PTC. Thyroid differentiation score (TDS) was calculated from 16 thyroid function genes. We demonstrated that ImmuneScore had a significant negative correlation with TDS, and BRAF

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

Tawfeek GA, Alhassanin S
HLA-G Gene Polymorphism in Egyptian Patients with Non-Hodgkin Lymphoma and its Clinical Outcome.
Immunol Invest. 2018; 47(3):315-325 [PubMed] Related Publications
BACKGROUND: Non-Hodgkin lymphoma (NHL) is a major cancer in Egypt and worldwide and has many risk factors including genes involved in the immune response.
AIM: we investigated the HLA-G 14bp gene polymorphism as a risk factor for NHL and its clinic pathologic features. The study involved 150 patients with NHL and 100 healthy control. Full histories, clinical examination, C.T scan and laboratory investigations such as CBC, LDH, ?2microglobulin and HCV RNA by qualitative real time PCR were performed for all subjects. HLA-G 14bp ins/del gene polymorphism was determined by PCR.
RESULTS: in our study, del/del, ins/del and dominant genotypes increased the risk of NHL by 11.01, 10.55 and 10.88 fold respectively (p<0.001) but the recessive genotype did not increase the risk of NHL (p=0.112). Cases with the del allele had a greater risk of NHL than those with the ins allele (p<0.001). del/del and ins/del genotypes were significantly associated with higher LDH and ?2microglobulin levels (p<0.001), lower Hb and platelet values (p<0.001), extra nodal sites (p=0.001), poor performance status (p=0.04) and relapse (p=0.001).  Conclusions:  the results suggest that HLA-G 14bp ins/del gene polymorphism is a risk factor for NHL in our Egyptian population and is associated with poor clinical pathological features.
ABBREVIATIONS: Non-Hodgkin lymphoma (NHL), Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Epstein-Barr virus (EBV), human T-cell lymphotropic/leukemia virus-1 (HTLV-1).

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] Article available free on PMC after 01/04/2020 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.

Melsted WN, Matzen SH, Andersen MH, Hviid TVF
The choriocarcinoma cell line JEG-3 upregulates regulatory T cell phenotypes and modulates pro-inflammatory cytokines through HLA-G.
Cell Immunol. 2018; 324:14-23 [PubMed] Related Publications
An understanding of the interactions between immune cells and trophoblast cells, as well as choriocarcinoma cells, are of extreme importance in reproductive immunology and cancer immunology. In this study, we found that the human HLA-G-positive choriocarcinoma cell line JEG-3 upregulates CD4

Crocchiolo R, Ringden O, Bay JO, et al.
Impact of HLA-G polymorphism on the outcome of allogeneic hematopoietic stem cell transplantation for metastatic renal cell carcinoma.
Bone Marrow Transplant. 2018; 53(2):213-218 [PubMed] Related Publications
Renal cell carcinoma (RCC) is particularly sensitive to immune intervention. HLA-G, a non-classical HLA class I molecule with immunomodulatory properties, has been studied with regard to outcome after hematopoietic stem cell transplantation (HSCT), in particular the 14 bp insertion/deletion polymorphism in the 3' untranslated region. Here we analyzed n=56 patients affected by metastatic RCC who received an allogeneic HSCT between 1998 and 2006 in Milano, Marseille, Clermont-Ferrand and Stockholm. The 14 bp polymorphism was analyzed in correlation with overall survival (OS), PFS, acute and chronic GvHD. With a median follow-up of 13 years, a trend towards better outcome was observed when homozygosity for the 14bp-del allele was present: multivariate hazard ratio was 0.50 (95% confidence interval (CI): 0.23-1.13; P=0.10) and 0.57 (95% CI: 0.26-1.26; P=0.17) for OS and PFS, respectively, when 14bp-del/del was compared with 14bp-ins/X. Further exploratory analysis revealed a significant association between T/C at p3003 and improved OS (P=0.05) and PFS (P=0.006) compared with T/T. To our knowledge this is the first study on HLA-G and outcome after HSCT for a solid malignancy. After a coordinated multicenter study, we found that the more tolerogenic polymorphisms (14bp-del/del) is associated with better PFS and OS. The finding on p3003 deserves further investigation.

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

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.

Caocci G, Greco M, Arras M, et al.
HLA-G molecules and clinical outcome in Chronic Myeloid Leukemia.
Leuk Res. 2017; 61:1-5 [PubMed] Related Publications
The human leukocyte antigen-G (HLA-G) gene encodes a tolerogenic protein known to promote tumor immune-escape. We investigated HLA-G polymorphisms and soluble molecules (sHLA-G) in 68 chronic myeloid leukemia (CML) patients. Patients with G*01:01:01 or G*01:01:02 allele had higher value of sHLA-G compared to G*01:01:03 (109.2±39.5 vs 39.9±8.8 units/ml; p=0.03), and showed lower event free survival (EFS) (62.3% vs 90.0%; p=0.02). The G*01:01:03 allele was associated with higher rates and earlier achievement of deep molecular response (MR)

Tronik-Le Roux D, Renard J, Vérine J, et al.
Novel landscape of HLA-G isoforms expressed in clear cell renal cell carcinoma patients.
Mol Oncol. 2017; 11(11):1561-1578 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Immune checkpoints are powerful inhibitory molecules that promote tumor survival. Their blockade is now recognized as providing effective therapeutic benefit against cancer. Human leukocyte antigen G (HLA-G), a recently identified immune checkpoint, has been detected in many types of primary tumors and metastases, in malignant effusions as well as on tumor-infiltrating cells, particularly in patients with clear cell renal cell carcinoma (ccRCC). Here, in order to define a possible anticancer therapy, we used a molecular approach based on an unbiased strategy that combines transcriptome determination and immunohistochemical labeling, to analyze in-depth the HLA-G isoforms expressed in these tumors. We found that the expression of HLA-G is highly variable among tumors and distinct areas of the same tumor, testifying a marked inter- and intratumor heterogeneity. Moreover, our results generate an inventory of novel HLA-G isoforms which includes spliced forms that have an extended 5'-region and lack the transmembrane and alpha-1 domains. So far, these isoforms could not be detected by any method available and their assessment may improve the procedure by which tumors are analyzed. Collectively, our approach provides the first extensive portrait of HLA-G in ccRCC and reveals data that should prove suitable for the tailoring of future clinical applications.

Garziera M, Scarabel L, Toffoli G
Hypoxic Modulation of HLA-G Expression through the Metabolic Sensor HIF-1 in Human Cancer Cells.
J Immunol Res. 2017; 2017:4587520 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
The human leukocyte antigen-G (HLA-G) is considered an immune checkpoint molecule involved in tumor immune evasion. Hypoxia and the metabolic sensor hypoxia-inducible factor 1 (HIF-1) are hallmarks of metastasization, angiogenesis, and intense tumor metabolic activity. The purpose of this review was to examine original in vitro studies carried out in human cancer cell lines, which reported data about HLA-G expression and HIF-1 mediated-HLA-G expression in response to hypoxia. The impact of

Seliger B
Immune modulatory microRNAs as a novel mechanism to revert immune escape of tumors.
Cytokine Growth Factor Rev. 2017; 36:49-56 [PubMed] Related Publications
Tumors have developed different strategies to escape immune recognition. This could be due to altered expression of classical and non-classical human leukocyte antigens (HLA), co-inhibitory or co-stimulatory molecules as well as components of the interferon signaling pathway. Furthermore, changes in the tumor microenvironment negatively interfere with anti-tumor immune responses and the frequency and activity of immune effector cells and professional antigen presenting cells (APC), while the number of immune suppressive cells is increased. Recently, microRNAs (miRNA) identified known as important players in the posttranscriptional regulation of gene expression have been demonstrated to be differentially expressed in tumors of distinct origin and present in nanovesicles secreted by tumors. They not only exhibit tumor suppressive and oncogenic potential, but also immune modulatory functions. This review focusses on the role of miRNA in posttranscriptional control of immune modulatory molecules in tumors and in exosomes, which might represent prognostic biomarkers and novel therapeutic targets.

Garziera M, Virdone S, De Mattia E, et al.
HLA-G 3'UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4) Chemotherapy in Non-Metastatic Colorectal Cancer.
Int J Mol Sci. 2017; 18(7) [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Polymorphisms in drug-metabolizing enzymes might not completely explain inter-individual differences in toxicity profiles of patients with colorectal cancer (CRC) that receive folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4). Recent data indicate that the immune system could contribute to FOLFOX4 outcomes. In light of the immune inhibitory nature of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, we aimed to identify novel genomic markers of grades 3 and 4 (G3-4) toxicity related to FOLFOX4 therapy in patients with CRC. We retrospectively analyzed data for 144 patients with stages II-III CRC to identify

da Silva IL, Veloso ES, Gonçalves INN, et al.
Qa-2 expression levels is related with tumor-infiltrating lymphocytes profile during solid Ehrlich tumor development.
Biomed Pharmacother. 2017; 92:750-756 [PubMed] Related Publications
The Qa-2 has been described as Human Leucocyte Antigen G (HLA-G) murine homolog. This homology is well accepted to gene and protein structure, in different pathology process and embryos implantation. However, in some neoplasm, this homology is questioned, where Qa-2 has been proposed as an immunogenic molecule, associated to tumor rejection. In this way, the aim of this study was to describe the pattern of Qa-2 expression and its relationship with the profile of tumor-infiltrating lymphocytes in solid Ehrlich tumor. The Ehrlich tumor growth was evaluated in Balb/c female mice in different tumor stages. The inflammatory infiltration features were determined by histopathology and, both lymphocyte type and tissue Qa-2 expression by immunohistochemistry. ELISA kit was used to determine soluble Qa-2 in the serum from the animals. We observed that Qa-2 in neoplastic cells increases in intermediate tumor development stages, while, serum Qa-2 increases in the late stage. Qa-2 increasing is correlated with CD3+ increase. Our results suggest that Qa-2 has a role opposite to HLA-G in Ehrlich solid carcinoma, and may be modulating the immune response by attracting the inflammatory infiltrate, especially T CD8+ Lymphocytes.

Martínez-Canales S, Cifuentes F, López De Rodas Gregorio M, et al.
Transcriptomic immunologic signature associated with favorable clinical outcome in basal-like breast tumors.
PLoS One. 2017; 12(5):e0175128 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Most patients with early stage triple negative breast cancer (TNBC) receive adjuvant chemotherapy. Activation of the immune system is associated with tumor response and may help identify TNBC with favorable outcome.
METHODS: Gene expression data were obtained from the GEO Dataset GDS2250/GSE3744. Affymetrix CEL files were downloaded and analyzed with Affymetrix Transcriptome Analysis Console 3.0. Functional genomics was implemented with David Bioinformatics Resources 6.8. Data contained at Oncomine were used to identify genes upregulated in basal-like cancer compared to normal breast tissue. Data contained at cBioportal were used to assess for molecular alterations. The KMPlotter online tool, METABRIC and GSE25066 datasets were used to associate gene signatures with clinical outcome.
RESULTS: 1564 upregulated genes were identified as differentially expressed between normal and basal-like tumors. Of these, 16 genes associated with immune function were linked with clinical outcome. HLA-C, HLA-F, HLA-G and TIGIT were associated with both improved relapse-free survival (RFS) and overall survival (OS). The combination of HLA-F/TIGIT and HLA-C/HLA-F/TIGIT showed the most favorable outcome (HR for RFS 0.44, p<0.001; HR for OS 0.22, p<0.001; and HR for RFS 0.46, p<0.001; HR for OS 0.15, p<0.001; respectively). The association of HLA-C/HLA-F with outcome was confirmed using the METABRIC and GSE25066 datasets. No copy number alterations of these genes were identified.
CONCLUSION: We describe a gene signature associated with immune function and favorable outcome in basal-like breast cancer. Incorporation of this signature in prospective studies may help to stratify risk of early stage TNBC.

Eichmüller SB, Osen W, Mandelboim O, Seliger B
Immune Modulatory microRNAs Involved in Tumor Attack and Tumor Immune Escape.
J Natl Cancer Inst. 2017; 109(10) [PubMed] Related Publications
Current therapies against cancer utilize the patient's immune system for tumor eradication. However, tumor cells can evade immune surveillance of CD8+ T and/or natural killer (NK) cells by various strategies. These include the aberrant expression of human leukocyte antigen (HLA) class I antigens, co-inhibitory or costimulatory molecules, and components of the interferon (IFN) signal transduction pathway. In addition, alterations of the tumor microenvironment could interfere with efficient antitumor immune responses by downregulating or inhibiting the frequency and/or functional activity of immune effector cells and professional antigen-presenting cells. Recently, microRNAs (miRNAs) have been identified as major players in the post-transcriptional regulation of gene expression, thereby controlling many physiological and also pathophysiological processes including neoplastic transformation. Indeed, the cellular miRNA expression pattern is frequently altered in many tumors of distinct origin, demonstrating the tumor suppressive or oncogenic potential of miRNAs. Furthermore, there is increasing evidence that miRNAs could also influence antitumor immune responses by affecting the expression of immune modulatory molecules in tumor and immune cells. Apart from their important role in tumor immune escape and altered tumor-host interaction, immune modulatory miRNAs often exert neoplastic properties, thus representing promising targets for future combined immunotherapy approaches. This review focuses on the characterization of miRNAs involved in the regulation of immune surveillance or immune escape of tumors and their potential use as diagnostic and prognostic biomarkers or as therapeutic targets.

Reeves E, James E
Tumour and placenta establishment: The importance of antigen processing and presentation.
Placenta. 2017; 56:34-39 [PubMed] Related Publications
Classical and non-classical MHC class I (MHC I) molecules displayed at the cell surface are essential for the induction of innate and adaptive immune responses. Classical MHC I present endogenously derived peptides to CD8

Takahashi H, Sakakura K, Kudo T, et al.
Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages.
Oncotarget. 2017; 8(5):8633-8647 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Stromal cells in the tumor microenvironment (TME) closely interact with tumor cells and affect tumor cell behavior in diverse manners. We herein investigated the mechanisms by which cancer-associated fibroblasts (CAFs) affect the functional polarization of tumor-associated macrophages (TAMs) in oral squamous cell carcinoma (OSCC) in vitro and in human cancer samples. The expression of CD68, CD14, CD163, CD200R, CD206, HLA-G, CD80, and CD86 was higher in CD14-positive cells co-cultured with the culture supernatants of CAFs established from OSCC specimens (CAF-educated cells) than in control cells. The gene expression level of ARG1, IL10, and TGFB1 was increased in CAF-educated cells. CAF-educated cells suppressed T cell proliferation more strongly than control cells, and the neutralization of TGF-β IL-10, or arginase I significantly restored T cell proliferation. We then investigated the relationship between the infiltration of CAFs and TAMs using tissue samples obtained from patients with OSCC. The infiltration of CAFs was associated with the numbers of CD68-positive and CD163-positive macrophages. It also correlated with lymphatic invasion, vascular invasion, lymph node involvement, and the TNM stage. The infiltration of CAFs was identified as an independent prognostic factor in OSCC. Our results indicate that CAFs play important roles in shaping the tumor immunosuppressive microenvironment in OSCC by inducing the protumoral phenotype of TAMs. Therapeutic strategies to reverse CAF-mediated immunosuppression need to be considered.

Agnihotri V, Gupta A, Kumar R, et al.
Promising link of HLA-G polymorphism, tobacco consumption and risk of Head and Neck Squamous Cell Carcinoma (HNSCC) in North Indian population.
Hum Immunol. 2017; 78(2):172-178 [PubMed] Related Publications
Human leukocyte antigen (HLA-G) is a potent immune-tolerant molecule and has a critical role in various pathological conditions of cancer. The aim of the study was to analyze the association of HLA-G polymorphism as a risk factor in Head and Neck Squamous Cell Carcinoma (HNSCC). The HLA-G polymorphism at 3'UTR 14bp INDEL (rs371194629) and +3142G/C (rs1063320) were studied in 383 HNSCC patients and 383 ethnically similar-aged healthy controls in North Indian population. The genotyping study of two polymorphisms of HLA-G was documented using DNA-PAGE and RFLP-PCR method. 14bp INDEL Del/Ins, Ins/Ins genotype and Ins allele were more pronounced in HNSCC patients in compared to controls. Whereas, +3142 C/C genotype and C allele were associated with risk factors in HNSCC. Furthermore, the dual effect of polymorphisms; both variants (Del/Ins-Ins/Ins & G/C-C/C) carrying loci was significantly (OR=2.78) associated with the disease compared to one variant (Del/Del-G/C or Del/Del-C/C or Ins/Ins-G/G). Moreover, both polymorphisms showed promising link in terms of tobacco influence on HNSCC risk. It can be concluded that this study first time reports that C/C, Del/Ins and Ins/Ins genotype as well as C and Ins allele could be major risk factors with strong impact of tobacco for HNSCC in North Indian population.

Johansen LL, Lock-Andersen J, Hviid TV
The Pathophysiological Impact of HLA Class Ia and HLA-G Expression and Regulatory T Cells in Malignant Melanoma: A Review.
J Immunol Res. 2016; 2016:6829283 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Malignant melanoma, a very common type of cancer, is a rapidly growing cancer of the skin with an increase in incidence among the Caucasian population. The disease is seen through all age groups and is very common in the younger age groups. Several studies have examined the risk factors and pathophysiological mechanisms of malignant melanoma, which have enlightened our understanding of the development of the disease, but we have still to fully understand the complex immunological interactions. The examination of the interaction between the human leucocyte antigen (HLA) system and prognostic outcome has shown interesting results, and a correlation between the down- or upregulation of these antigens and prognosis has been seen through many different types of cancer. In malignant melanoma, HLA class Ia has been seen to influence the effects of pharmaceutical drug treatment as well as the overall prognosis, and the HLA class Ib and regulatory T cells have been correlated with tumor progression. Although there is still no standardized immunological treatment worldwide, the interaction between the human leucocyte antigen (HLA) system and tumor progression seems to be a promising focus in the way of optimizing the treatment of malignant melanoma.

Cordeiro JC, da Silva JS, Roxo VS, da Graça Bicalho M
A pilot study on Hla-G locus control region haplotypes and cervical intraepithelial neoplasias.
Hum Immunol. 2017; 78(3):281-286 [PubMed] Related Publications
Human papillomavirus (HPV) can induce cervical intraepithelial neoplasias (CIN) grades 1, 2 and 3. Untreated, these lesions may progress to cervical cancer (CC) which is the third most common cancer in women worldwide. HLA-G plays an immunotolerant role in the immune response. The aim of this study was to characterize the configuration of SNPs located at the distal promoter of HLA-G in patients with CIN2 and CIN3 and control women. The study sample was composed of 207 women as follows: 73 diagnosed with CIN2 lesions, 56 with CIN3 and 78 healthy control women. Genotyping was performed by sequence base typing. Eleven haplotype configurations subdivided in two main haplogroups (H1dist and H2dist), were characterized and compared between patients and controls. The haplotypes H1.1Dist (GAGAACGC) and H2.1Dist (AGGTACAC) were more frequent in Euro-Descendants as well as in Brazilian Mixed. Nevertheless, the haplotype H2.1Dist standed out as a susceptibility haplotype in Brazilian Mixed patients while the H1.1Dist presented a protector effect in this same ethnic group. Whether such LCR haplotype configurations can impact on HLA-G gene expression levels in women who developed cervical intraepithelial neoplasia is still unknown and it is of utmost importance that more investigation on this field be pursued.

de Figueiredo-Feitosa NL, Martelli Palomino G, Cilião Alves DC, et al.
HLA-G 3' untranslated region polymorphic sites associated with increased HLA-G production are more frequent in patients exhibiting differentiated thyroid tumours.
Clin Endocrinol (Oxf). 2017; 86(4):597-605 [PubMed] Related Publications
BACKGROUND: HLA-G is a nonclassical class I histocompatibility molecule implicated on the immune escape mechanism of tumour cells. We evaluated the genetic diversity of HLA-G 3' untranslated region (3'UTR) and associated polymorphic sites with clinical presentation and with the magnitude of HLA-G thyroid expression.
PATIENTS AND METHODS: Polymorphic sites at 3'UTR (14bpINS/DEL, +3003C/T, +3010C/G, +3027A/C, +3035C/T, +3142C/G, +3187A/G, +3196C/G) were characterized by sequencing analyses in blood samples of 72 patients exhibiting papillary thyroid carcinoma (PTC), 22 follicular thyroid carcinomas (FTC), 19 follicular adenomas (FA), 21 colloid goitres and 156 healthy controls.
RESULTS: Compared to goitre and/or controls, patients with PTC exhibited higher frequency of 14bpDEL (P = 0·030), +3010G (P = 0·034), +3010CG (P = 0·044), +3142CG (P = 0·040), +3035C (P = 0·050) and +3187GG (P = 0·032). Patients with FTC presented higher frequency of 14bpINS/DEL (P = 0·020). The UTR-5 haplotype was underrepresented in PTC (P = 0·050). The +3003TT was more frequent in patients with PTC older than 45 years (P = 0·030). Male patients had a higher frequency of +3196GG (P = 0·040). Tumour multicentricity was associated with UTR-2 (P = 0·030). The following associations were observed in PTC and FTC combined: i) tumour size <2 cm with 14bpINS/INS (P = 0·030); ii) multicentricity with +3035CC (P = 0·030) and +3196GG (P = 0·030); iii) decreased thyroid HLA-G expression with +3196C and +3196CC; and iv) moderate HLA-G thyroid staining with UTR-2.
CONCLUSIONS: HLA-G 3'UTR polymorphisms associated with a greater magnitude of HLA-G production were associated with differentiated thyroid tumours and with variables implicated in poor prognosis. These findings corroborate the unfavourable role of HLA-G in thyroid cancer.

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] Article available free on PMC after 01/04/2020 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.

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.

Coelho AV, Moura RR, Crovella S, Celsi F
HLA-G genetic variants and hepatocellular carcinoma: a meta-analysis.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
Human leukocyte antigen (HLA)-G is a key tolerogenic molecule mainly expressed in the placenta and is crucial for implantation of the embryo and immunological tolerance of the fetus during pregnancy. However, under pathological conditions, such as cancer or viral infections, HLA-G can be expressed in other tissues. The gene coding for HLA-G (HLA-G, chromosome 6p21.3) presents numerous polymorphisms, some of them influencing its expression. One of the most studied, is the 14 bp ins/del (rs371194629) situated at the 3'-UTR of the gene. The insertion is thought to stabilize HLA-G mRNA. Different studies have analyzed the role of rs371194629 in hepatic injury, with either hepatotropic virus infection (i.e., HBV or HCV) or hepatocellular carcinoma (also induced by viral infection). Results from these studies are heterogeneous, differing with ethnicity and population age, and the role of rs371194629 is unclear. For these reasons, we decided to perform a meta-analysis of these results, concluding that the 14-bp ins/del polymorphism does not significantly contribute to hepatic injury.

Yaghi L, Poras I, Simoes RT, et al.
Hypoxia inducible factor-1 mediates the expression of the immune checkpoint HLA-G in glioma cells through hypoxia response element located in exon 2.
Oncotarget. 2016; 7(39):63690-63707 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
HLA-G is an immune checkpoint molecule with specific relevance in cancer immunotherapy. It was first identified in cytotrophoblasts, protecting the fetus from maternal rejection. HLA-G tissue expression is very restricted but induced in numerous malignant tumors such as glioblastoma, contributing to their immune escape. Hypoxia occurs during placenta and tumor development and was shown to activate HLA-G. We aimed to elucidate the mechanisms of HLA-G activation under conditions combining hypoxia-mimicking treatment and 5-aza-2'deoxycytidine, a DNA demethylating agent used in anti-cancer therapy which also induces HLA-G. Both treatments enhanced the amount of HLA-G mRNA and protein in HLA-G negative U251MG glioma cells. Electrophoretic Mobility Shift Assays and luciferase reporter gene assays revealed that HLA-G upregulation depends on Hypoxia Inducible Factor-1 (HIF-1) and a hypoxia responsive element (HRE) located in exon 2. A polymorphic HRE at -966 bp in the 5'UT region may modulate the magnitude of the response mediated by the exon 2 HRE. We suggest that therapeutic strategies should take into account that HLA-G expression in response to hypoxic tumor environment is dependent on HLA-G gene polymorphism and DNA methylation state at the HLA-G locus.

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