Gene Summary

Gene:HLA-C; major histocompatibility complex, class I, C
Aliases: MHC, HLAC, HLC-C, D6S204, PSORS1, HLA-JY3
Summary:HLA-C 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. Class I molecules play a central role in the immune system by presenting peptides derived from endoplasmic reticulum lumen. They are expressed in nearly all 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 exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. Over one hundred HLA-C alleles have been described [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:HLA class I histocompatibility antigen, Cw-1 alpha chain
Source:NCBIAccessed: 16 March, 2017


What does this gene/protein do?
Show (22)
Pathways:What pathways are this gene/protein implicaed in?
Show (4)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 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.

  • Melanoma
  • Homologous Transplantat
  • Mexico
  • Case-Control Studies
  • Genes, MHC Class I
  • Single Nucleotide Polymorphism
  • HLA-DR Antigens
  • HLA Antigens
  • Receptors, KIR
  • Young Adult
  • Receptors, KIR2DL2
  • Childhood Cancer
  • Haplotypes
  • Chromosome 6
  • T-Lymphocytes
  • HLA-C Antigens
  • Pedigree
  • Genotype
  • Retinoblastoma
  • Genetic Predisposition
  • Phenotype
  • Polymerase Chain Reaction
  • Transplantation
  • DNA Sequence Analysis
  • Virus Integration
  • Hematopoietic Stem Cell Transplantation
  • Pancreatic Cancer
  • HLA-A
  • Uterine Cancer
  • Base Sequence
  • Histocompatibility Testing
  • Spain
  • Natural Killer Cells
  • Adolescents
  • Genetic Recombination
  • Sequence Homology, Nucleic Acid
  • Vaccination
  • Alleles
  • T-Lymphocytes, Cytotoxic
  • HLA-B
  • Cervical Cancer
  • Urinary Bladder
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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-C (cancer-related)

Suzawa K, Shien K, Peng H, et al.
Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies.
Anticancer Res. 2017; 37(1):301-307 [PubMed] Related Publications
BACKGROUND: Reduced expression in immortalized cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and its overexpression by adenovirus vector (Ad-REIC) exhibits a remarkable therapeutic effect on various human cancer types through a mechanism triggered by endoplasmic reticulum stress.
MATERIALS AND METHODS: We examined the direct anti-tumor effect of Ad-REIC gene therapy on lung cancer and malignant mesothelioma cell lines in vitro, and the distant bystander effect using immunocompetent mouse allograft models with bilateral flank tumors.
RESULTS: Ad-REIC treatment showed antitumor effect in many lung cancer and malignant mesothelioma cell lines in vitro. In an in vivo model, Ad-REIC treatment inhibited the growth not only of directly treated tumors but also of distant untreated tumors. By immunohistochemical analysis, infiltration of T-cells and natural killer (NK) cells and expression of the major histocompatibility complex (MHC) class I molecules were observed in bilateral tumors.
CONCLUSION: Ad-REIC treatment not only had a direct antitumor effect but also an indirect bystander effect through stimulation of the immune system.

Huang CF, Huang CY, Yeh ML, et al.
Genetics Variants and Serum Levels of MHC Class I Chain-related A in Predicting Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients Post Antiviral Treatment.
EBioMedicine. 2017; 15:81-89 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIMS: The genome-wide association study has shown that MHC class I chain-related A (MICA) genetic variants were associated with hepatitis C virus (HCC) related hepatocellular carcinoma. The impact of the genetic variants and its serum levels on post-treatment cohort is elusive.
METHODS: MICA rs2596542 genotype and serum MICA (sMICA) levels were evaluated in 705 patients receiving antiviral therapy.
RESULTS: Fifty-eight (8·2%) patients developed HCC, with a median follow-up period of 48·2months (range: 6-129months). The MICA A allele was associated with a significantly increased risk of HCC development in cirrhotic non-SVR patients but not in patients of non-cirrhotic and/or with SVR. For cirrhotic non-SVR patients, high sMICA levels (HR/CI: 5·93/1·86-26.38·61, P=0·002) and the MICA rs2596542 A allele (HR/CI: 4·37/1·52-12·07, P=0·002) were independently associated with HCC development. The risk A allele or GG genotype with sMICA>175ng/mL provided the best accuracy (79%) and a negative predictive value of 100% in predicting HCC.
CONCLUSIONS: Cirrhotic patients who carry MICA risk alleles and those without risk alleles but with high sMICA levels possessed the highest risk of HCC development once they failed antiviral therapy.

Meng Y, Hu J, Chen Y, et al.
Silencing MARCH1 suppresses proliferation, migration and invasion of ovarian cancer SKOV3 cells via downregulation of NF-κB and Wnt/β-catenin pathways.
Oncol Rep. 2016; 36(5):2463-2470 [PubMed] Free Access to Full Article Related Publications
Membrane-associated RING-CH (MARCH) belongs to the family of RING-CH type E3 ubiquitin ligases. MARCH1 ubiquitinates and downregulates MHC class II expression in APCs and targets major players of the immune system. However, the role of MARCH1 in ovarian cancer has not been elucidated. The present study investigated the function of MARCH1 in ovarian cancer and the potential mechanisms involved. MARCH1 expression was examined in human ovarian cancer tissue specimens by immunohistochemistry. The role of MARCH1 in ovarian cancer cells was assessed by cell proliferation, migration and invasion assays with MARCH1 gene silencing. To investigate the mechanism by which MARCH1 functions, correlation between MARCH1 and the cell signaling pathways were analyzed using a luciferase reporter assay, real-time RT-PCR, western blot assay and immunofluorescence. MARCH1 was found to be overexpressed in ovarian cancer tissues when compared to adjacent non-tumor and normal ovarian tissues. Silencing MARCH1 inhibited SKOV3 cell proliferation, invasion and migration, as well as inhibiting the NF-κB and the Wnt/β‑catenin pathways. MARCH1 functions as a tumor promoter by upregulating the NF-κB and the Wnt/β-catenin pathways, indicating that MARCH1 may be a therapeutic target for patients with ovarian cancer.

Liu W, Almo SC, Zang X
Co-stimulate or Co-inhibit Regulatory T Cells, Which Side to Go?
Immunol Invest. 2016; 45(8):813-831 [PubMed] Related Publications
Co-stimulatory and co-inhibitory molecules direct the "second signal," which largely determines the outcome of the "first signal" generated by the interaction of T cell receptor (TCR) with cognate MHC-peptide complex. The co-stimulatory and co-inhibitory signals are key mechanistic contributors to the regulation of adaptive immunity, especially the T cell-mediated immune response. Regulatory T cells (Tregs) are a special population of T cells, which unlike other T cells function as "attenuators" to suppress T cell immunity. Dysregulation of either the "second signal" or Tregs leads to an unbalanced immune system, which can result in a range of immune-related disorders, including autoimmune diseases, chronic infections, and tumors. In contrast, precise manipulation of these two systems offers tremendous clinical opportunities to treat these same diseases. Co-stimulatory and co-inhibitory molecules modulate immunity at molecular level, whereas Tregs delicately control the immune response at cellular level. Accumulating evidence has demonstrated that these two regulatory strategies converge and synergize with each other. This review discusses recent progress on the roles of co-stimulatory and co-inhibitory signals in the context of Tregs.

Fan LL, Xue XZ, Jiao N
In vitro effect of IL-17D on human ovarian carcinoma cells and inherent immunity.
J Biol Regul Homeost Agents. 2016 Jul-Sep; 30(3):815-820 [PubMed] Related Publications
This study explored the expression of interleukin 17D (IL-17D) secreted by human ovariancarcinoma cells and the effect of exogenous IL-17D transfection on MICA, which is the ligand of NKG2D, on the surface of ovary carcinoma cells. Human ovarian papillary serous adenocarcinoma cell line SKOV3, empty vector control cell line SKOV3/vector, exogenous human IL-17D stable-transfected cell line SKOV3/IL-17D, as well as cisplatin (CDDP)-resistant cell SKOV/CDDP were cultured; ovarian adenocarcinoma cell line OVCAR-3, empty vector control cell line OVCAR3/vector and OVCAE3/IL- 17D were observed under a microscope. In the study, methyl-thiazolyl-tetrazolium (MTT) method was used to detect the inhibition rate, resistance index and proliferation of SKOV3 and SKOV3/CDDP. It was found that the expression of IL-17 D in SKOV3/CDDP was much higher than that of its parent cell line SKOV3; IL-17D might be correlated to the drug resistance of cells; the proliferation of SKOV3 transfected with IL-17D was significantly accelerated, indicating IL-17D may be effective in promoting the growth of oncocyte.

Salmaninejad A, Zamani MR, Pourvahedi M, et al.
Cancer/Testis Antigens: Expression, Regulation, Tumor Invasion, and Use in Immunotherapy of Cancers.
Immunol Invest. 2016; 45(7):619-40 [PubMed] Related Publications
UNLABELLED: Cancer/testis antigens (CTAs) are named based on their expression pattern that is restricted in a number of normal and abnormal tissues. Tumor cells frequently express antigens whose expression is typically restricted to germ cells. Their unique expression pattern is guaranteed by precise epigenetic regulatory mechanisms. Because of their tumor-limited, high immunogenicity, and biased expression, discovery of these molecules provides unprecedented opportunities for further research and clinical development in the field of cancer diagnosis and immunotherapy. Evolving evidence reveals that a number of CTAs stimulate epithelial mesenchymal transition (EMT) and generation of cancer stem-like cells, intensifying metastasis, invasion, and tumorigenesis. Based on these features, CTAs attract attention to be considered as ideal targets for developing several clinical trials, many of them concentrating on CTA vaccine therapy. According to recent practical clinical interest, more characterizations of CTA regulation are identified. CTA expression has been demonstrated in a variety of human cancer tissues, and some of them have been found to elicit humoral and/or cellular immune responses in cancer patients. CTAs are brilliant targets for anticancer drug discovery, targeted tumor therapy, and diagnostic biomarkers, furthermore, valued genes in the study of immunotherapy, promoting tumorigenesis, and malignant progression. This review outlines and categorizes our current understanding of the complex and biased process of CTAs mRNA and protein expression in cancer, and supplies the most recent information on their regulation and function. Besides, a concise synopsis of the major clinical trials involving CTAs, as therapeutic avenues, is discussed.
ABBREVIATIONS: AIRE: autoimmune regulator; cAMP: cyclic adenosine 3',5'-cyclic monophosphate; CEA: carcinoembryonic antigen; CML: chronic myeloid leukemia; CREB: cyclicamp response element binding; CSCs: cancer stem cells; CTAs: cancer/testis antigens; CTL: cytotoxic T lymphocyte; DCs: dendritic cells; EMT: epithelial-mesenchymal transition; ERK: extracellular signal-regulated kinase; ESCC: esophageal squamous cell carcinoma; ETS: E26 transformation-specific; His: histidine; HLA: human leukocyte antigen; HNSCC: head and neck squamous cell carcinoma; IFN-γ: interferon-γ; IHC: Immunohistochemistry; IL-7: Interleukin7; MHC: major histocompatibility complex; MMP2: matrix metalloproteinase 2; mTECs: medullary thymus epithelial cells; MUC1: mucin 1; NSCLC: non-small cell lung cancer; PRAME: preferentially expressed antigen in melanoma; RDA: representational difference analysis; SEREX: serological analysis of cDNA expression; SSX: synovial sarcoma X chromosome; TAAs: tumor-associated antigens; TCR: T-cell receptor; TCGA: The Cancer Genome Atlas; TGF-β: transforming growth factor-β.

Okada K, Hakata S, Terashima J, et al.
Combination of the histone deacetylase inhibitor depsipeptide and 5-fluorouracil upregulates major histocompatibility complex class II and p21 genes and activates caspase-3/7 in human colon cancer HCT-116 cells.
Oncol Rep. 2016; 36(4):1875-85 [PubMed] Free Access to Full Article Related Publications
Epigenetic anticancer drugs such as histone deacetylase (HDAC) inhibitors have been combined with existing anticancer drugs for synergistic or additive effects. In the present study, we found that a very low concentration of depsipeptide, an HDAC inhibitor, potentiated the antitumor activity of 5-fluorouracil (5-FU) in a human colon cancer cell model using HCT-116, HT29, and SW48 cells via the inhibition of colony formation ability or cellular viability. Exposure to a combination of 5-FU (1.75 µM) and 1 nM depsipeptide for 24 and 48 h resulted in a 3- to 4-fold increase in activated caspase-3/7, while 5-FU alone failed to activate caspase-3/7. Microarray and subsequent gene ontology analyses revealed that compared to 5-FU or depsipeptide alone, the combination treatment of 5-FU and depsipeptide upregulated genes related to cell death and the apoptotic process consistent with the inhibition of colony formation and caspase-3/7 activation. These analyses indicated marked upregulation of antigen processing and presentation of peptide or polysaccharide antigen via major histocompatibility complex (MHC) class (GO:0002504) and MHC protein complex (GO:0042611). Compared with vehicle controls, the cells treated with the combination of 5-FU and depsipeptide showed marked induction (3- to 8.5-fold) of expression of MHC class II genes, but not of MHC class I genes. Furthermore, our global analysis of gene expression, which was focused on genes involved in the molecular regulation of MHC class II genes, showed enhancement of pro-apoptotic PCAF and CIITA after the combination of 5-FU and depsipeptide. These results may indicate a closer relationship between elevation of MHC class II expression and cellular apoptosis induced by the combination of depsipeptide and 5-FU. To the best of our knowledge, this is the first study to report that the combination of 5-FU and depsipeptide induces human colon cancer cell apoptosis in a concerted manner with the induction of MHC class II gene expression.

Dhanik A, Kirshner JR, MacDonald D, et al.
In-silico discovery of cancer-specific peptide-HLA complexes for targeted therapy.
BMC Bioinformatics. 2016; 17:286 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA) Class I molecules bind to peptide fragments of proteins degraded inside the cell and display them on the cell surface. We are interested in peptide-HLA complexes involving peptides that are derived from proteins specifically expressed in cancer cells. Such complexes have been shown to provide an effective means of precisely targeting cancer cells by engineered T-cells and antibodies, which would be an improvement over current chemotherapeutic agents that indiscriminately kill proliferating cells. An important concern with the targeting of peptide-HLA complexes is off-target toxicity that could occur due to the presence of complexes similar to the target complex in cells from essential, normal tissues.
RESULTS: We developed a novel computational strategy for identifying potential peptide-HLA cancer targets and evaluating the likelihood of off-target toxicity associated with these targets. Our strategy combines sequence-based and structure-based approaches in a unique way to predict potential off-targets. The focus of our work is on the complexes involving the most frequent HLA class I allele HLA-A*02:01. Using our strategy, we predicted the off-target toxicity observed in past clinical trials. We employed it to perform a first-ever comprehensive exploration of the human peptidome to identify cancer-specific targets utilizing gene expression data from TCGA (The Cancer Genome Atlas) and GTEx (Gene Tissue Expression), and structural data from PDB (Protein Data Bank). We have thus identified a list of 627 peptide-HLA complexes across various TCGA cancer types.
CONCLUSION: Peptide-HLA complexes identified using our novel strategy could enable discovery of cancer-specific targets for engineered T-cells or antibody based therapy with minimal off-target toxicity.

Zaretsky JM, Garcia-Diaz A, Shin DS, et al.
Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.
N Engl J Med. 2016; 375(9):819-29 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Approximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown.
METHODS: We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later.
RESULTS: Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.
CONCLUSIONS: In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.).

Wang X, Ding M, Yang Y, et al.
Personalized discovery of altered pathways in clear cell renal cell carcinoma using accumulated normal sample data.
J BUON. 2016 Mar-Apr; 21(2):390-8 [PubMed] Related Publications
PURPOSE: To identify altered pathways in an individual with clear cell renal cell carcinoma (ccRCC) using accumulated normal sample data.
METHODS: Gene expression data of E-GEOD-40435 was downloaded from the ArrayExpress database. Gene-level statistics of genes in tumor and normal samples were computed. Then, the Average Z method was applied to calculate the individual pathway aberrance score (iPAS). Subsequently, the significantly altered pathways in a ccRCC sample were identified using T-test based on the pathway statistics values of normal and ccRCC samples. Moreover, the identified altered pathways were verified through two methods: one was assessing classification capability for microarray data samples, and the other was computing the changed percentage of each pathway in ccRCC samples.
RESULTS: Based on the threshold, 886 altered pathways were identified in all samples. The most significant pathways were potassium transport channels, proton-coupled monocarboxylate transport, beta oxidation of octanoyl-CoA to hexanoyl-CoA, antigen presentation: folding, assembly and peptide loading of class I MHC, and so on. Additionally, iPAS separated ccRCC from normal controls with an accuracy of 0.980. Moreover, a total of 5 significant pathways with change in 100% ccRCC samples were extracted including proton-coupled monocarboxylate transport, antigen presentation: folding, assembly and peptide loading of class I MHC, and so on.
CONCLUSIONS: iPAS is useful to predict marker pathways for ccRCC with a high accuracy. Pathways of proton-coupled monocarboxylate transport, and antigen presentation: folding, assembly and peptide loading of class I MHC might play crucial roles in ccRCC progression.

Rathika C, Murali V, Dhivakar M, et al.
Susceptible and Protective Associations of HLA Alleles and Haplotypes with Cervical Cancer in South India.
Asian Pac J Cancer Prev. 2016; 17(5):2491-7 [PubMed] Related Publications
BACKGROUND: Human leukocyte antigen (HLA) genes have been implicated in cervical cancer in several populations.
OBJECTIVES: To study the predispositions of HLA alleles/haplotypes with cervical cancer.
MATERIALS AND METHODS: Clinically diagnosed and PAP smear confirmed cervical cancer patients (n 48) and age matched controls (n 47) were genotyped for HLA-A,-B,-DRB1* and DQB1* alleles by PCR-SSP methods.
RESULTS: The frequencies of alleles DRB1*04 (OR=2.57), DRB1*15 (OR=2.04), DQB1*0301 (OR=4.91), DQB1*0601 (OR=2.21), B*15 (OR=13.03) and B*07 (OR=6.23) were higher in cervical cancer patients than in the controls. The frequencies of alleles DRB1*10 (OR=0.22) and B*35 (OR=0.19) were decreased. Strong disease associations were observed for haplotypes DRB1*15-DQB1*0601 (OR=6.56; < 3.5.10-4), DRB1*14-DQB1*0501 (OR=6.51; <0.039) and A*11-B*07 (OR=3.95; <0.005). The reduced frequencies of haplotypes DRB1*10-DQB1*0501 (OR=0.45), A*03-B*35 (OR=0.25) and A*11-B*35 (OR= 0.06) among patients suggested a protective association. HLA-C* typing of 8 patients who possessed a unique three locus haplotype 'A*11-B*07-DRB1*04' (8/48; 16.66%; OR=6.51; <0.039) revealed the presence of a four locus haplotype 'A*11-B*07-C*01-DRB1*04' in patients (4/8; 50%). Amino acid variation analysis of susceptible allele DQB1*0601 suggested 'tyrosine' at positions β9 and β37 and tyrosine-non-tyrosine genotype combination increased the risk of cervical cancer.
CONCLUSIONS: Strong susceptible associations were documented for HLA alleles B*15, B*07, DRB1*04, DRB1*15, DQB1*0301, DQB1*0601 and haplotypes DRB1*15-DQB1*0601 and DRB1*14-DQB1*0501. Further, protective associations were evidenced for alleles B*35 and DRB1*10 and haplotypes A*11-B*35 and DRB1*10-DQB1*0501 with cervical cancer in South India.

Yoshihama S, Roszik J, Downs I, et al.
NLRC5/MHC class I transactivator is a target for immune evasion in cancer.
Proc Natl Acad Sci U S A. 2016; 113(21):5999-6004 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Cancer cells develop under immune surveillance, thus necessitating immune escape for successful growth. Loss of MHC class I expression provides a key immune evasion strategy in many cancers, although the molecular mechanisms remain elusive. MHC class I transactivator (CITA), known as "NLRC5" [NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5], has recently been identified as a critical transcriptional coactivator of MHC class I gene expression. Here we show that the MHC class I transactivation pathway mediated by CITA/NLRC5 constitutes a target for cancer immune evasion. In all the 21 tumor types we examined, NLRC5 expression was highly correlated with the expression of MHC class I, with cytotoxic T-cell markers, and with genes in the MHC class I antigen-presentation pathway, including LMP2/LMP7, TAP1, and β2-microglobulin. Epigenetic and genetic alterations in cancers, including promoter methylation, copy number loss, and somatic mutations, were most prevalent in NLRC5 among all MHC class I-related genes and were associated with the impaired expression of components of the MHC class I pathway. Strikingly, NLRC5 expression was significantly associated with the activation of CD8(+) cytotoxic T cells and patient survival in multiple cancer types. Thus, NLRC5 constitutes a novel prognostic biomarker and potential therapeutic target of cancers.

Geldres C, Savoldo B, Dotti G
Chimeric Antigen Receptors for Cancer Immunotherapy.
Methods Mol Biol. 2016; 1393:75-86 [PubMed] Related Publications
The adoptive transfer of T lymphocytes expressing chimeric antigen receptors (CARs) has emerged as a promising treatment for various lymphoid and solid malignancies. Patients treated with CAR-T cells have achieved dramatic responses and in some cases, complete tumor eradication. Given that CARs combine the specificity of a monoclonal antibody with the internal signaling domains of T cells, there is flexibility for choice of target antigen and strength of T-cell activation. This targeting mechanism also relinquishes the need for antigen processing and presentation via the major histocompatibility complex (MHC), making CARs a very attractive therapeutic option for the majority of patients. This review describes current methodological strategies used to generate CAR molecules, how to insert these molecules in T lymphocytes and how to evaluate the functionality of these CAR-T cells using various in vitro and in vivo experiments.

Bargostavan MH, Eslami G, Esfandiari N, Shams Shahemabadi A
MMP9 Promoter Polymorphism (-1562 C/T) Does not Affect the Serum Levels of Soluble MICB and MICA in Breast Cancer.
Iran J Immunol. 2016; 13(1):45-53 [PubMed] Related Publications
BACKGROUND: The role of Matrix Metalloproteinase 9 (MMP9) in tumor invasion and progression is prominent. A single nucleotide polymorphism (SNP) in the promoter region of MMP9 (-1562 C/T) increases the transcription and expression of this gene. On the other hand, MHC class I chain-related protein A and B (MICA/B) in soluble forms may impair tumor immunogenicity by reducing Natural Killer Group 2D (NKG2D) densities on NK cells and MMP9 enzyme activity has a prominent role in shedding of MICA/B.
OBJECTIVES: To investigate the association between MMP9 (-1562 C/T) polymorphism and serum MICA/B level in breast cancer patients.
METHODS: In this case-control study, 105 patients with breast cancer and 100 healthy age-matched women were selected from Yazd hospitals, Iran. The polymorphism of MMP9 (-1562 C/T) was determined by PCR-RFLP. Concentration of MICB and MICA in the sera of breast cancer patients and healthy women were measured using ELISA method.
RESULTS: The frequency of CC, CT and TT genotypes and T allele of the MMP9 (-1562 C/T) did not show significant differences between breast cancer patients and healthy donors (p>0.05). On the other hand, the mean serum levels of MICB and MICA were significantly elevated in patients compared with healthy individuals (p<0.05). In patients with MMP9CC genotype, the mean serum MICB concentration was significantly higher than those patients with CT polymorphism (p<0.05). Although the mean of blood MICA concentration in patients with the CT genotype was higher than those patients with CC genotype, the difference was not statistically significant.
CONCLUSION: The T allele of the MMP9 (-1562 C/T) does not show a correlation with serum levels of MICA and MICB in breast cancer patients.

Sun W, Gui L, Zuo X, et al.
Human epithelial-type ovarian tumour marker beta-2-microglobulin is regulated by the TGF-β signaling pathway.
J Transl Med. 2016; 14:75 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Beta-2-microglobulin (B2M), a light chain subunit of the major histocompatibility complex (MHC) class I complex, has been implicated in tumorigenesis. However, whether it is expressed in different epithelial-type ovarian tumours remains unknown. This study was performed to examine the expression of B2M in different histopathological types of ovarian tumours, to explore the function of B2M in ovarian cancer (OC) cells and to investigate the mechanisms underlying the regulation of B2M by the TGF-β signaling pathway.
METHODS: B2M expression in normal ovarian tissues and epithelia-type ovarian tumours was detected by immunohistochemistry and Western blot, followed by the analysis of association with clinical features. OC cells were transfected with B2M-siRNA and cell proliferation, migration and invasion were determined by WST-1 assay, wound healing assay and Transwell invasion assay, respectively. The regulation of B2M by the TGF-β signaling pathway in OC cells was examined by Western blot, ELISA and qRT-PCR.
RESULTS: We found that B2M was overexpressed in ovarian borderline and malignant tumours compared with benign tumours and normal controls, but was not associated with age, tumour size, lymph node metastasis and clinical stage. Knocking down of B2M led to a decrease in OC cell proliferation, migration and invasion. The expression of B2M was downregulated by TGF-β1 in OC cells, which was abolished in the presence of the inhibitor of TGF-β type I receptor.
CONCLUSION: Our findings suggest that B2M is a potential tissue biomarker and therapeutic target of borderline and malignant ovarian tumours and the dysregulation of B2M in these tumours may be mediated by the TGF-β signaling pathway.

Forero A, Li Y, Chen D, et al.
Expression of the MHC Class II Pathway in Triple-Negative Breast Cancer Tumor Cells Is Associated with a Good Prognosis and Infiltrating Lymphocytes.
Cancer Immunol Res. 2016; 4(5):390-9 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Triple-negative breast cancer (TNBC) is a subtype with heterogeneous patient outcomes. Approximately 40% of patients experience rapid relapse, while the remaining patients have long-term disease-free survival. To determine if there are molecular differences between primary tumors that predict prognosis, we performed RNA-seq on 47 macrodissected tumors from newly diagnosed patients with TNBC (n = 47; 22 relapse, 25 no relapse; follow-up median, 8 years; range, 2-11 years). We discovered that expression of the MHC class II (MHC II) antigen presentation pathway in tumor tissue was the most significant pathway associated with progression-free survival (HR, 0.36; log-rank P = 0.0098). The association between MHC II pathway expression and good prognosis was confirmed in a public gene expression database of 199 TNBC cases (HR, 0.28; log-rank P = 4.5 × 10(-8)). Further analysis of immunohistochemistry, laser-capture microdissected tumors, and TNBC cell lines demonstrated that tumor cells, in addition to immune cells, aberrantly express the MHC II pathway. MHC II pathway expression was also associated with B-cell and T-cell infiltration in the tumor. Together, these data support the model that aberrant expression of the MHC II pathway in TNBC tumor cells may trigger an antitumor immune response that reduces the rate of relapse and enhances progression-free survival. Cancer Immunol Res; 4(5); 390-9. ©2016 AACR.

Vermeulen JF, van Hecke W, Spliet WG, et al.
Pediatric Primitive Neuroectodermal Tumors of the Central Nervous System Differentially Express Granzyme Inhibitors.
PLoS One. 2016; 11(3):e0151465 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
BACKGROUND: Central nervous system (CNS) primitive neuroectodermal tumors (PNETs) are malignant primary brain tumors that occur in young infants. Using current standard therapy, up to 80% of the children still dies from recurrent disease. Cellular immunotherapy might be key to improve overall survival. To achieve efficient killing of tumor cells, however, immunotherapy has to overcome cancer-associated strategies to evade the cytotoxic immune response. Whether CNS-PNETs can evade the immune response remains unknown.
METHODS: We examined by immunohistochemistry the immune response and immune evasion strategies in pediatric CNS-PNETs.
RESULTS: Here, we show that CD4+, CD8+, γδ-T-cells, and Tregs can infiltrate pediatric CNS-PNETs, although the activation status of cytotoxic cells is variable. Pediatric CNS-PNETs evade immune recognition by downregulating cell surface MHC-I and CD1d expression. Intriguingly, expression of SERPINB9, SERPINB1, and SERPINB4 is acquired during tumorigenesis in 29%, 29%, and 57% of the tumors, respectively.
CONCLUSION: We show for the first time that brain tumors express direct granzyme inhibitors (serpins) as a potential mechanism to overcome cellular cytotoxicity, which may have consequences for cellular immunotherapy.

Wang Z, Liu N, Shi S, et al.
The Role of PIWIL4, an Argonaute Family Protein, in Breast Cancer.
J Biol Chem. 2016; 291(20):10646-58 [PubMed] Article available free on PMC after 13/05/2017 Related Publications
P-element-induced wimpy testis (PIWI) proteins bind to PIWI-interacting RNAs and play key roles in the biogenesis and functions of PIWI-interacting RNAs. It has been reported that PIWI proteins are essential for stem cell self-renewal and germline development in diverse organisms and that they are ectopically expressed in multiple forms of cancer. However, the role of PIWI in cancer remains elusive. Here we report that one of the four PIWI proteins in humans, PIWIL4, is highly expressed in both breast cancer tissues and the cytoplasm of MDA-MB-231 cells derived from breast cancer. Reducing PIWIL4 expression drastically impairs the migration ability of MDA-MB-231 cells, significantly increases their apoptosis, and mildly affects their proliferation. Our transcriptome and proteome analysis reveal that these functions are at least partially achieved via the PIWIL4 regulation of TGF-β and FGF signaling pathways and MHC class II proteins. These findings suggest that PIWIL4 may serve as a potential therapeutic target for breast cancer.

Colangelo T, Polcaro G, Ziccardi P, et al.
Proteomic screening identifies calreticulin as a miR-27a direct target repressing MHC class I cell surface exposure in colorectal cancer.
Cell Death Dis. 2016; 7:e2120 [PubMed] Article available free on PMC after 13/05/2017 Related Publications
Impairment of the immune response and aberrant expression of microRNAs are emerging hallmarks of tumour initiation/progression, in addition to driver gene mutations and epigenetic modifications. We performed a preliminary survey of independent adenoma and colorectal cancer (CRC) miRnoma data sets and, among the most dysregulated miRNAs, we selected miR-27a and disclosed that it is already upregulated in adenoma and further increases during the evolution to adenocarcinoma. To identify novel genes and pathways regulated by this miRNA, we employed a differential 2DE-DIGE proteome analysis. We showed that miR-27a modulates a group of proteins involved in MHC class I cell surface exposure and, mechanistically, demonstrated that calreticulin is a miR-27a direct target responsible for most downstream effects in epistasis experiments. In vitro miR-27a affected cell proliferation and angiogenesis; mouse xenografts of human CRC cell lines expressing different miR-27a levels confirmed the protein variations and recapitulated the cell growth and apoptosis effects. In vivo miR-27a inversely correlated with MHC class I molecules and calreticulin expression, CD8(+) T cells infiltration and cytotoxic activity (LAMP-1 exposure and perforin release). Tumours with high miR-27a, low calreticulin and CD8(+) T cells' infiltration were associated with distant metastasis and poor prognosis. Our data demonstrate that miR-27a acts as an oncomiRNA, represses MHC class I expression through calreticulin downregulation and affects tumour progression. These results may pave the way for better diagnosis, patient stratification and novel therapeutic approaches.

Ritter C, Fan K, Paulson KG, et al.
Reversal of epigenetic silencing of MHC class I chain-related protein A and B improves immune recognition of Merkel cell carcinoma.
Sci Rep. 2016; 6:21678 [PubMed] Article available free on PMC after 13/05/2017 Related Publications
Merkel cell carcinoma (MCC) is a virally associated cancer characterized by its aggressive behavior and strong immunogenicity. Both viral infection and malignant transformation induce expression of MHC class I chain-related protein (MIC) A and B, which signal stress to cells of the immune system via Natural Killer group 2D (NKG2D) resulting in elimination of target cells. However, despite transformation and the continued presence of virally-encoded proteins, MICs are only expressed in a minority of MCC tumors in situ and are completely absent on MCC cell lines in vitro. This lack of MIC expression was due to epigenetic silencing via MIC promoter hypo-acetylation; indeed, MIC expression was re-induced by pharmacological inhibition of histone deacetylases (HDACs) both in vitro and in vivo. This re-induction of MICs rendered MCC cells more sensitive to immune-mediated lysis. Thus, epigenetic silencing of MICs is an important immune escape mechanism of MCCs.

Kumar S, Stokes J, Singh UP, et al.
Targeting Hsp70: A possible therapy for cancer.
Cancer Lett. 2016; 374(1):156-66 [PubMed] Related Publications
In all organisms, heat-shock proteins (HSPs) provide an ancient defense system. These proteins act as molecular chaperones by assisting proper folding and refolding of misfolded proteins and aid in the elimination of old and damaged cells. HSPs include Hsp100, Hsp90, Hsp70, Hsp40, and small HSPs. Through its substrate-binding domains, Hsp70 interacts with wide spectrum of molecules, ranging from unfolded to natively folded and aggregated proteins, and provides cytoprotective role against various cellular stresses. Under pathophysiological conditions, the high expression of Hsp70 allows cells to survive with lethal injuries. Increased Hsp70, by interacting at several points on apoptotic signaling pathways, leads to inhibition of apoptosis. Elevated expression of Hsp70 in cancer cells may be responsible for tumorigenesis and for tumor progression by providing resistance to chemotherapy. In contrast, inhibition or knockdown of Hsp70 reduces the size of tumors and can cause their complete regression. Moreover, extracellular Hsp70 acts as an immunogen that participates in cross presentation of MHC-I molecules. The goals of this review are to examine the roles of Hsp70 in cancer and to present strategies targeting Hsp70 in the development of cancer therapeutics.

Li H, Liu F, Zhu H, et al.
Interaction Between Polymorphisms of IFN-γ and MICA Correlated with Hepatocellular Carcinoma.
Med Sci Monit. 2016; 22:549-53 [PubMed] Article available free on PMC after 13/05/2017 Related Publications
BACKGROUND We explored the relationship of interferon-γ (IFN-γ) and MHC class-I chain related gene A (MICA) genes polymorphisms with hepatocellular carcinoma (HCC) risk, and tried to determine whether the interaction existed between these two genes polymorphisms on the basis of HCC. MATERIAL AND METHODS Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect the genotypes of the 3 single-nucleotide polymorphisms (SNPs) and to analyze the correlation of each SNP with HCC susceptibility in 120 HCC patients and 124 healthy people. The association strength between the 3 SNPs and HCC is represented with odds ratio (OR) and 95% confidence interval (95% CI). Hardy-Weinberg equilibrium (HWE) was tested by χ2 test in the control group. RESULTS GG genotype of IFN-γ rs2069727 polymorphism had apparently different distributions in case and control groups (P<0.05), and might confer increased risk of HCC (OR=3.40, 95%CI=1.23-9.38). Analysis of MICA rs2596542 polymorphism also yielded the same result (OR=2.90, 95%CI=1.10-7.67), as did their risk alleles. Specifically, the interaction between rs2596542 and rs2069705 polymorphisms increased the HCC risk by 1.41 times and between rs2596542 and rs2069727 polymorphisms the increased risk of HCC by 5.56 times. CONCLUSIONS IFN-γ rs2069727 and MICA rs2596542 polymorphisms may be related to the incidence of HCC. Interaction exists between the polymorphisms of IFN-γ and MICA, which may increase risk of HCC.

Tesone AJ, Rutkowski MR, Brencicova E, et al.
Satb1 Overexpression Drives Tumor-Promoting Activities in Cancer-Associated Dendritic Cells.
Cell Rep. 2016; 14(7):1774-86 [PubMed] Article available free on PMC after 13/05/2017 Related Publications
Special AT-rich sequence-binding protein 1 (Satb1) governs genome-wide transcriptional programs. Using a conditional knockout mouse, we find that Satb1 is required for normal differentiation of conventional dendritic cells (DCs). Furthermore, Satb1 governs the differentiation of inflammatory DCs by regulating major histocompatibility complex class II (MHC II) expression through Notch1 signaling. Mechanistically, Satb1 binds to the Notch1 promoter, activating Notch expression and driving RBPJ occupancy of the H2-Ab1 promoter, which activates MHC II transcription. However, tumor-driven, unremitting expression of Satb1 in activated Zbtb46(+) inflammatory DCs that infiltrate ovarian tumors results in an immunosuppressive phenotype characterized by increased secretion of tumor-promoting Galectin-1 and IL-6. In vivo silencing of Satb1 in tumor-associated DCs reverses their tumorigenic activity and boosts protective immunity. Therefore, dynamic fluctuations in Satb1 expression govern the generation and immunostimulatory activity of steady-state and inflammatory DCs, but continuous Satb1 overexpression in differentiated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression.

Sanz-Pamplona R, Gil-Hoyos R, López-Doriga A, et al.
Mutanome and expression of immune response genes in microsatellite stable colon cancer.
Oncotarget. 2016; 7(14):17711-25 [PubMed] Article available free on PMC after 13/05/2017 Related Publications
The aim of this study was to analyze the impact of the mutanome in the prognosis of microsatellite stable stage II CRC tumors. The exome of 42 stage II, microsatellite stable, colon tumors (21 of them relapse) and their paired mucosa were sequenced and analyzed. Although some pathways accumulated more mutations in patients exhibiting good or poor prognosis, no single somatic mutation was associated with prognosis. Exome sequencing data is also valuable to infer tumor neoantigens able to elicit a host immune response. Hence, putative neoantigens were identified by combining information about missense mutations in each tumor and HLAs genotypes of the patients. Under the hypothesis that neoantigens should be correctly presented in order to activate the immune response, expression levels of genes involved in the antigen presentation machinery were also assessed. In addition, CD8A level (as a marker of T-cell infiltration) was measured. We found that tumors with better prognosis showed a tendency to generate a higher number of immunogenic epitopes, and up-regulated genes involved in the antigen processing machinery. Moreover, tumors with higher T-cell infiltration also showed better prognosis. Stratifying by consensus molecular subtype, CMS4 tumors showed the highest association of expression levels of genes involved in the antigen presentation machinery with prognosis. Thus, we hypothesize that a subset of stage II microsatellite stable CRC tumors are able to generate an immune response in the host via MHC class I antigen presentation, directly related with a better prognosis.

Cai H, Degliangeli F, Palitzsch B, et al.
Glycopeptide-functionalized gold nanoparticles for antibody induction against the tumor associated mucin-1 glycoprotein.
Bioorg Med Chem. 2016; 24(5):1132-5 [PubMed] Related Publications
We report the preparation of gold nanoparticle (AuNP)-based vaccine candidates against the tumor-associated form of the mucin-1 (MUC1) glycoprotein. Chimeric peptides, consisting of a glycopeptide sequence derived from MUC1 and the T-cell epitope P30 sequence were immobilized on PEGylated AuNPs and the ability to induce selective antibodies in vivo was investigated. After immunization, mice showed significant MHC-II mediated immune responses and their antisera recognized human MCF-7 breast cancer cells. Nanoparticles designed according to this report may become key players in the development of anticancer vaccines.

Cheung KJ, Padmanaban V, Silvestri V, et al.
Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters.
Proc Natl Acad Sci U S A. 2016; 113(7):E854-63 [PubMed] Article available free on PMC after 13/05/2017 Related Publications
Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14(+) cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14(+) epithelial tumor cell clusters disseminate collectively to colonize distant organs.

Johnson DB, Estrada MV, Salgado R, et al.
Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy.
Nat Commun. 2016; 7:10582 [PubMed] Article available free on PMC after 13/05/2017 Related Publications
Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of 'PD-1 signalling', 'allograft rejection' and 'T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4(+) and CD8(+) tumour infiltrate. MHC-II(+) tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection.

Nicol SM, Sabbah S, Brulois KF, et al.
Primary B Lymphocytes Infected with Kaposi's Sarcoma-Associated Herpesvirus Can Be Expanded In Vitro and Are Recognized by LANA-Specific CD4+ T Cells.
J Virol. 2016; 90(8):3849-59 [PubMed] Article available free on PMC after 13/05/2017 Related Publications
UNLABELLED: Kaposi's sarcoma-associated herpesvirus (KSHV) has tropism for B lymphocytes, in which it establishes latency, and can also cause lymphoproliferative disorders of these cells manifesting as primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). T cell immunity is vital for the control of KSHV infection and disease; however, few models of B lymphocyte infection exist to study immune recognition of such cells. Here, we developed a model of B lymphocyte infection with KSHV in which infected tonsillar B lymphocytes were expanded by providing mitogenic stimuli and then challenged with KSHV-specific CD4(+)T cells. The infected cells expressed viral proteins found in PELs, namely, LANA and viral IRF3 (vIRF3), albeit at lower levels, with similar patterns of gene expression for the major latency, viral interleukin 6 (vIL-6), and vIRF3 transcripts. Despite low-level expression of open reading frame 50 (ORF50), transcripts for the immune evasion genes K3 and K5 were detected, with some downregulation of cell surface-expressed CD86 and ICAM. The vast majority of infected lymphocytes expressed IgM heavy chains with Igλ light chains, recapitulating the features seen in infected cells in MCD. We assessed the ability of the infected lymphocytes to be targeted by a panel of major histocompatibility complex (MHC) class II-matched CD4(+)T cells and found that LANA-specific T cells restricted to different epitopes recognized these infected cells. Given that at least some KSHV latent antigens are thought to be poor targets for CD8(+)T cells, we suggest that CD4(+)T cells are potentially important effectors for thein vivocontrol of KSHV-infected B lymphocytes.
IMPORTANCE: KSHV establishes a latent reservoir within B lymphocytes, but few models exist to study KSHV-infected B cells other than the transformed PEL cell lines, which have likely accrued mutations during the transformation process. We developed a model of KSHV-infected primary B lymphocytes that recapitulates features seen in PEL and MCD by gene expression and cell phenotype analysis, allowing the study of T cell recognition of these cells. Challenge of KSHV-infected B cells with CD4(+)T cells specific for LANA, a protein expressed in all KSHV-infected cells and malignanciesin vivo, showed that these effectors could efficiently recognize such targets. Given that the virus expresses immune evasion genes or uses proteins with intrinsic properties, such as LANA, that minimize epitope recognition by CD8(+)T cells, CD4(+)T cell immunity to KSHV may be important for maintaining the virus-host balance.

Wanram S, Sombatwong J, Sakunpong A, et al.
Comparison of Automated and Conventional IHC Visual Scoring Analysis for MHC Class I and Tapasin Expression in Cervical Carcinoma.
J Med Assoc Thai. 2016; 99 Suppl 1:S67-75 [PubMed] Related Publications
BACKGROUND: Cervical cancer (CXCA) is the second most common cancer among women in Thailand and worldwide. Immune evasion caused by down-regulation of host immune responsive genes, such as MHC class I and loss of antigen processing machinery (APM), presents a capability leading to cancer development. Immunohistochemical staining (HC) is regarded as a common technique for protein marker detection in clinical laboratories. At present, IHC automation has been launched to facilitate the speed and feasibility to replace conventional IHC. However, evaluation of its use is still limited.
OBJECTIVE: This study aimed to evaluate IHC scoring by automated visual analysis compared to conventional IHC analysis.
MATERIAL AND METHOD: The paraffin-embedded tissues of 96 invasive CXCA were processed using a tissue microarray (TMA) platform followed by automated IHC staining of the anti-MHC class I (heavy chain, β2M) and an APM-Tapasin expression. Conventional IHC and automated slide scanning with scoring visual analysis were compared.
RESULTS: The results showed significant association between conventional and automated IHC evaluation (p-value > 0.05, Chi-square) for MHC class I and Tapasin stated in percentage of positive cancer cells, whereas intensity was found (p-value < 0.05, Chi-square) with moderate agreement (p-value < 0.001, kappa) 0.434-0.615 and 0.353-0.554, respectively. After calculated values, the results showed significant association between conventional and automated IHC evaluation (p-value > 0.05, Chi-square) for MHC class I and Tapasin with the highest agreement level (p-value < 0.001, kappa) of summation 0.595-0.755 and multiply scoring 0.633-0.689, respectively.
CONCLUSION AND DISCUSSION: The automation softwarefor IHC scoring and interpretation can be used for the determination of MHC class I and Tapasin in CXCA. In addition, an antigen presentation pattern must be included to allow an accurate result for MHC class I in clinical use. An appropriate sample size and design of staging coverage as well as clinical prognosis outcomes of progression should be used infurther investigation.

Morishima S, Kashiwase K, Matsuo K, et al.
High-risk HLA alleles for severe acute graft-versus-host disease and mortality in unrelated donor bone marrow transplantation.
Haematologica. 2016; 101(4):491-8 [PubMed] Article available free on PMC after 13/05/2017 Related Publications
HLA molecules play an important role for immunoreactivity in allogeneic hematopoietic stem cell transplantation. To elucidate the effect of specific HLA alleles on acute graft-versus-host disease, we conducted a retrospective analysis using 6967 Japanese patients transplanted with T-cell-replete marrow from an unrelated donor. Using unbiased searches of patient and donor HLA alleles, patient and/or donor HLA-B*51:01 (patient: HR, 1.37,P<0.001; donor: HR, 1.35,P<0.001) and patient HLA-C*14:02 (HR, 1.35,P<0.001) were significantly associated with an increased risk of severe acute graft-versus-host disease. The finding that donor HLA-C*14:02 was not associated with severe acute graft-versus-host disease prompted us to elucidate the relation of these high-risk HLA alleles with patient and donor HLA-C allele mismatches. In comparison to HLA-C allele match, patient mismatched HLA-C*14:02 showed the highest risk of severe acute graft-versus-host disease (HR, 3.61,P<0.001) and transplant-related mortality (HR, 2.53,P<0.001) among all patient mismatched HLA-C alleles. Although patient HLA-C*14:02 and donor HLA-C*15:02 mismatch was usually KIR2DL-ligand mismatch in the graft-versus-host direction, the risk of patient mismatched HLA-C*14:02 for severe acute graft-versus-host disease was obvious regardless of KIR2DL-ligand matching. The effect of patient and/or donor HLA-B*51:01 on acute graft-versus-host disease was attributed not only to strong linkage disequilibrium of HLA-C*14:02 and -B*51:01, but also to the effect of HLA-B*51:01 itself. With regard to clinical implications, patient mismatched HLA-C*14:02 proved to be a potent risk factor for severe acute graft-versus-host disease and mortality, and should be considered a non-permissive HLA-C mismatch in donor selection for unrelated donor hematopoietic stem cell transplantation.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. HLA-C, Cancer Genetics Web: http://www.cancer-genetics.org/HLA-C.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 16 March, 2017     Cancer Genetics Web, Established 1999