HLA-G expression in malignant melanoma.
ABSTRACT Both, the expression of HLA-G (a non-classical HLA class I molecule) and the loss of classical HLA class I molecules enable tumor cells to evade from immunosurveillance of the host. Whereas HLA-G down-modulates the immune functions of all cells participating in the immune defence mechanisms, defects on HLA class I expression result in the resistance of tumor cells to cytotoxic T lymphocytes attacks. This contribution reviews the HLA-G expression pattern in malignant melanoma lesions, its correlation to the loss of classical HLA class I antigens, and new aspects of HLA-G regulation.
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ABSTRACT: BACKGROUND: The causal association between persistent human papillomavirus (HPV) infection and cervical cancer has been established, but the mechanisms that favor HPV persistence in cervical cells are still unknown. The diminished capability of the immune system to control and resolve HPV infection is one of several hypotheses. The tolerogenic protein HLA-G has shown aberrant expression in a variety of cancers, which has been suggested as a mechanism for tumor escape from immunosurveillance. In the present study we evaluate the role of epigenetic modification (promoter de-methylation) of the HLA-G gene on susceptibility to HPV infection and development of high-grade cervical lesions. METHODS: A case--control study was carried out in Curitiba, Brazil, between February and June 2010. A total of 789 women aged 15--47 years were recruited: 510 controls with normal cervical cytology, and 279 cases with histologically confirmed cervical intraepithelial neoplasia grade 2 (CIN2, N = 150) or grade 3 (CIN3, N = 129). All women were administered a questionnaire by interview, which collected information on demographic and lifestyle factors, and a cervical sample was collected. HPV DNA detection was performed by GP5+/GP6+ primer-mediated PCR. HPV-positive samples were genotyped by multiplex PCR. A pilot analysis of HLA-G promoter methylation was carried out in a subset of the study population (96 cases and 76 controls) by pyrosequencing. HLA-G methylation and HPV infection status of cases and controls were compared, and confounding factors were computed by t Student and non-parametric Wilcoxon tests. Comparison of HLA-G methylation between cases and controls was assessed by the Bonferroni correction. The association of HLA-G methylation with CIN2/3 was evaluated by logistic regression. RESULTS: HPV prevalence was 19.6 % in controls and 94.3 % in CIN2/3 cases. HPV16, 31, 33, 35 and 18 were the most prevalent types. Methylation analysis of seven CpGs in the HLA-G promoter did not reveal any spontaneous de-methylation events in CIN2/3 cases (mean proportion of methylation: 75.8 %) with respect to controls (mean 73.7 %; odds ratio 1.01, 95 % confidence interval 0.96, 1.07). CONCLUSIONS: This study did not support the hypothesis that spontaneous de-methylation events in the HLA-G promoter play a primary role in promoting escape from immunosurveillance in the development of precancerous cervical lesions.BMC Cancer 12/2012; 12(1):618. DOI:10.1186/1471-2407-12-618 · 3.32 Impact Factor
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ABSTRACT: The human leukocyte antigen (HLA)-G is a tolerogenic molecule, whose expression by allografts is associated with better acceptance. An increasing interest in producing HLA-G as a clinical-grade molecule for therapy use is impaired by its complexity and limited stability. Our purpose was to engineer simpler and more stable HLA-G-derived molecules than the full-length HLA-G trimolecular complex that are also tolerogenic, functional as soluble molecules, and compatible with good manufacturing practice (GMP) production conditions. We present two synthetic molecules: (α3-L)x2 and (α1-α3)x2 polypeptides. We show their capability to bind the HLA-G receptor LILRB2 and their functions in vitro and in vivo. The (α1-α3)x2 polypeptide proved to be a potent tolerogenic molecule in vivo: One treatment of skin allograft recipient mice with (α1-α3)x2 was sufficient to significantly prolong graft survival, and four weekly treatments induced complete tolerance. Furthermore, (α1-α3)x2 was active as a soluble molecule and capable of inhibiting the proliferation of tumor cell lines, as does the full length HLA-G trimolecular complex. Thus, the synthetic (α1-α3)x2 polypeptide is a stable and simpler alternative to the full-length HLA-G molecule. It can be produced under GMP conditions, it functions as a soluble molecule, and it is at least as tolerogenic as HLA-G in vivo.-LeMaoult, J., Daouya, M., Wu, J., Loustau, M., Horuzsko, A., Carosella, E. D. Synthetic HLA-G proteins for therapeutic use in transplantation.The FASEB Journal 06/2013; 27(9). DOI:10.1096/fj.13-228247 · 5.48 Impact Factor
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ABSTRACT: Natural killer (NK) cells are critical components of our immune system. Herein, we for the first time analyzed the expression and localization of the activating receptor NK cell lectin-like receptor gene 2D (NKG2D) ligands, HLA-G, MICA, MICA/B, and ULBP-2 in orthotopic transplantation models of retinoblastoma. Interestingly, HLA-G and MICA/B were expressed in retinoblastoma cell, whereas MICA and ULBP-2 were not detected. Moreover, HLA-G and MICA/B were primarily detected in proliferative area of the tumor periphery with high Ki-67 immunostaining. Our results suggest that NKG2D ligands are differentially expressed in retinoblastoma, which would play a crucial role in immunomodulation in retinoblastoma.Cancer Investigation 11/2012; DOI:10.3109/07357907.2012.743554 · 2.06 Impact Factor