HLA-G is a component of the chronic lymphocytic leukemia escape repertoire to generate immune suppression: impact of the HLA-G 14 base pair (rs66554220) polymorphism

Rizzo, Roberta; Audrito, Valentina; Vacca, Paola; Rossi, Davide; Brusa, Davide; Stignani, Marina; Bortolotti, Daria; D’Arena, Giovanni; Coscia, Marta; Laurenti, Luca; Forconi, Francesco; Gaïdano, Gianluca; Mingari, Maria Cristina; Moretta, Alessandro; Malavasi, Fabio; Deaglio, Silvia

doi:10.3324/haematol.2013.095281

Cited by 44 publications

(43 citation statements)

References 38 publications

(34 reference statements)

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“…33,46 Only recently have these analyses been broadened to other polymorphisms in the 3'UTR region of HLA-G and to membrane-bound HLA-G. 47,48 In the present study, we screened the association of multiple variations in the 3'UTR HLA-G, considering alleles, genotypes, haplotypes, and diplotypes, with membrane-bound HLA-G expression on DC-10. We found that the majority of donors with HLA-G low DC-10 carried haplotypes, such as UTR-2, UTR-5, UTR-7, containing 14bp Ins and G in position +3142, both variations previously associated with low mRNA stability.…”

Section: Discussionmentioning

confidence: 99%

HLA-G expression levels influence the tolerogenic activity of human DC-10

et al. 2015

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ABSTRACTand CD8 low suppressor T cells, 25 interleukin-10 (IL-10)-producing T regulatory type 1 (Tr1) cells, DC-10 are a subset of human tolerogenic DC that are present in vivo [27][28][29] and can be differentiated in vitro by culturing monocytes in the presence of IL-10. DC-10 secrete IL-10, are CD11c + , express CD14, CD16, HLA-G and ILT4 and, although not activated, display a mature phenotype, being CD86+ and HLA-DR + . The secretion of IL-10 and the expression of membrane-bound HLA-G and ILT4 are critical factors involved in DC-10-mediated induction of Tr1 cells. 27 In the present study, we investigated the role of HLA-G in DC-10-mediated Tr1 cell induction and whether polymorphisms present at the 3'UTR of the gene influence the expression of membrane-bound HLA-G on DC-10. MethodsThe methods are described in full in the Online Supplementary Appendix. Peripheral blood was obtained after informed consent in accordance with the Declaration of Helsinki under protocols approved by the ethical committee of the San Raffaele Telethon Institute for Gene Therapy. Dendritic cell differentiation CD14+ monocytes were isolated from peripheral blood mononuclear cells by positive selection using CD14 MicroBeads (Miltenyi Biotech, Germany) according to the manufacturer's instructions. Cells were cultured in RPMI 1640 (Lonza, Italy) supplemented with 10% fetal bovine serum (FBS) (Lonza, Italy) or with 5% human serum (HS) (EuroClone, Italy), 100 U/mL penicillin/streptomycin (Lonza, Italy), 2 mM L-glutamine (Lonza, Italy), (DC medium) at 37°C in the presence of 10 ng/mL recombinant human (rh)IL-4 (R&D Systems, Minneapolis MN, USA) and 100 ng/mL rhGM-CSF (Genzyme, Seattle, WA, USA) with 10 ng/mL of rhIL-10 (BD, Bioscience, CA, USA) for 7 days to differentiate DC-10. Cells cultured with rhIL-4 and rhGM-CSF on day 5 were matured with 1 mg/mL of lipopolysaccharide (Sigma, CA, USA) for 2 more days to generate mature dendritic cells (mDC). At day 7, DC were collected, phenotypically analyzed, and used to stimulate T cells. Statistical analysisSample mean results were compared using the non-parametric Mann-Whitney U test for continuous variables. HLA-G 3'UTR allele and genotype frequencies were obtained by direct counting. Allele and genotype frequencies between populations were compared using the χ 2 test. The correlation between membranebound HLA-G and ILT4 expression was determined using the Spearman correlation test. FBS and DC-10 HS were compared using a paired t-test. All results are presented as mean values ± standard error of mean (SEM). Differences were regarded as statistically significant at *P<0.05, **P<0.01, and ***P<0.001. The results were analyzed using GraphPad Prism 5.0 (GraphPad Software, Inc. La Jolla, CA, USA). Results In vitro differentiated DC-10 express variable levels of membrane-bound HLA-GIndependently of the donor, DC-10 differentiated in vitro as described in the Methods section were Figure 1A,B). High variability in the expression of membrane-bound HLA-G (ranging from 3.5% to 97.7%) and of ILT4 (rangin...

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Section: Discussionmentioning

confidence: 99%

HLA-G expression levels influence the tolerogenic activity of human DC-10

et al. 2015

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“…In this context, a possible association of HLA-G gene polymorphism with susceptibility and/or clinical outcome of malignancies was documented. A 14-base pair insertion/deletion (ins/del) polymorphism (rs66554220) in the 3′ UTR was revealed; both chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL) patients with the del/del genotype had shorter survival than patients with the ins/del or ins/ ins genotype (102,103). Additionally, DLBCL patients who carry the HLA-G-725CC genotype in the 5′ URR had a significantly higher probability of overall survival than individuals with other genotype combinations of HLA-G-725C/G/T (103).…”

Section: Relevance Of Hla-g Expression In Cancersmentioning

confidence: 99%

Human Leukocyte Antigen-G (HLA-G) Expression in Cancers: Roles in Immune Evasion, Metastasis and Target for Therapy

Lin

Yan

2015

Mol Med

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Aberrant induction of human leukocyte antigen-G (HLA-G) expression has been observed in various malignancies and is strongly associated with tumor immune escape, metastasis and poor prognosis. To date, great achievements have been made in understanding the underlying mechanisms of HLA-G involved in tumor progression. HLA-G could lead to tumor evasion by inhibition of immune cell cytolysis, differentiation and proliferation and inhibition of cytokine production, induction of immune cell apoptosis, generation of regulatory cells and expansion of myeloid-derived suppressive cells and by impairment of chemotaxis. Moreover, HLA-G could arm tumor cells with a higher invasive and metastatic potential with the upregulation of tumor-promoting factor expression such as matrix metalloproteinases (MMPs), indicating that ectopic HLA-G expression could render multiple effects during the progression of malignancies. In this review, we summarized the mechanisms of HLA-G involved in promoting tumor cell immune escaping, metastasis and disease progression. Special attention will be paid to its significance as an attractive therapeutic target in cancers.

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“…Patients having this genotype revealed a reduced overall survival [6]. Here, HLA-G expression correlated with the number of regulatory T-cells (Tregs) [6] and is involved in the protection of B-CLL cells from NK-mediated killing [6,7]. In multiple myeloma (MM) HLA-G expression on malignant plasma cells was also associated with a poor prognosis [8].…”

Section: First Situation: Hla-g Expression Is Related To Worse Prognosismentioning

confidence: 99%

“…Very recently, it was evidenced that the HLA-G expression on B-CLLs was associated to a homozygous deletion of 14 base pairs within the 3'-untranslated region of HLA-G gene being related to stable mRNA and protein expression. Patients having this genotype revealed a reduced overall survival [6]. Here, HLA-G expression correlated with the number of regulatory T-cells (Tregs) [6] and is involved in the protection of B-CLL cells from NK-mediated killing [6,7].…”

Section: First Situation: Hla-g Expression Is Related To Worse Prognosismentioning

confidence: 99%

“…There is no data on HLA-G or ILT2 expression by tissue CLL. However, if tissue CLL cells express HLA-G but not ILT2, HLA-G would inhibit T-or NK-cells exactly as evidenced recently [6,7]. In this configuration, the overall effect of HLA-G would indeed impair the anti-tumor response, and a correlation between HLA-G presence and bad prognosis would be observed.…”

Section: Differences In Ilt2 Expression and Function By Tumor Cellsmentioning

confidence: 99%

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