HLA—G与肿瘤关系研究

HLA—G是一种非经典人类白细胞抗原。近年研究认为HLA—G作为免疫耐受分子，在肿瘤免疫逃逸中可能具有重要作用。现综述HLA—G的基因结构特点、在不同肿瘤中的表达情况及其临床意义和目前研究存在的问题。     

HLA-G与肿瘤免疫逃逸作用

人白细胞抗原（human leukocyte antigen，HLA）是位于人第6号染色体短臂上的一群高度多态性的紧密连锁基因群，HLA—G属于非经典HLA—Ⅰ类分=产（HLA—Ⅰb，HLA—G、E、F），是惟一表达于母胎界面滋养层的HLA—Ⅰ类基因，参与母胎免疫耐受的形成。但是在肿瘤微环境中，肿瘤细胞产生的HLA—G可以结合NK和T细胞表面的杀伤细胞抑制受体（killing inhibitory receptor，KIR），强烈抑制T细胞和NK细胞对肿瘤靶细胞的识别、杀伤等活性，造成类似妊娠母胎界面的免疫耐受状态，形成一条新的肿瘤逃逸途径。     

HLA-G与肿瘤免疫逃逸

HLAG是一种非经典的HLAI类抗原。在人类黑色素瘤、乳腺癌、结肠癌、胰腺癌、膀胱癌、肾癌和肺癌中可表达HLAG。HLAG可以通过抑制NK细胞、CTL细胞等效应细胞的作用，改变机体细胞因子分泌的模式来抑制机体的肿瘤免疫反应，使肿瘤细胞发生免疫逃逸而得以生存发展。     

HLA分型及其在个体化肿瘤肽疫苗中的应用

恶性肿瘤临床治疗已经进入肿瘤综合性治疗和个体化治疗的时代,肿瘤免疫治疗也是目前肿瘤治疗研究的热点之一,尤其是个体化肿瘤肽疫苗已成为肿瘤治疗的一种新思路。人类白细胞抗原(HLA)分子和抗原决定簇的良好结合是个体化肿瘤肽疫苗、肿瘤肽刺激的树突状细胞瘤苗及体外培养后回输的抗原特异性T细胞能否产生抗肿瘤免疫作用的关键因素。本文介绍了HLA与个体化肿瘤肽疫苗的关系并分析目前HLA相关的个体化肿瘤肽疫苗的临床研究情况及我国人群HLA分布。     

非经典HLA-Ⅰ类分子HLA-G在肿瘤免疫逃逸中的作用

HLA G是非经典的HLA Ⅰ类基因 ,其编码产物的组织分布有限 ,主要分布在母胎组织的接触界面 ,在一些肿瘤中也有分布。多态性相对不明显 ,可通过与杀伤细胞抑制受体 (KIR)结合 ,发挥抑制NK细胞和T细胞的效应。     

肿瘤的HLA相关生物治疗

人类白细胞抗原(HLA)作为人类最复杂、最具多态性的遗传系统，其功能涉及到机体免疫的各个方面，肿瘤的发生发展和HLA有非常重要的关系，因此HLA相关的肿瘤生物治疗成为近年来肿瘤研究的热点，包括发现和鉴定某HLA基因型匹配的、CD8^ T细胞所识别的肿瘤特异性抗原肽，寻找CD4^ T细胞所识别的抗原肽，针对HLA表型缺失的不同原因而采取的各种HLA基因治疗，以及对HLA分子表达异质性和动态性等的研究，各项研究的进展将为肿瘤的免疫基因治疗提供更科学的理论依据。     

肿瘤的HLA相关生物治疗

人类白细胞抗原(HLA)作为人类最复杂、最具多态性的遗传系统,其功能涉及到机体免疫的各个方面,肿瘤的发生发展和HLA有非常重要的关系,因此HLA相关的肿瘤生物治疗成为近年来肿瘤研究的热点,包括发现和鉴定某HLA基因型匹配的、CD8+T细胞所识别的肿瘤特异性抗原肽,寻找CD4+T细胞所识别的抗原肽,针对HLA表型缺失的不同原因而采取的各种HLA基因治疗,以及对HLA分子表达异质性和动态性等的研究,各项研究的进展将为肿瘤的免疫基因治疗提供更科学的理论依据.     

Cullin3在肿瘤中的研究进展

泛素一蛋白酶体系统（ubiquitin—proteasome system,UPS）是蛋白质翻译后调控的重要途径,能够维持机体内蛋白质水平的平衡。Cullin3（Cul3）作为支架蛋白参与构成泛素连接酶复合物,通过与具有BTB（bric—abrac,tramtrack,and broad complex）结构域的接头蛋白结合,特异性识别底物并介导底物泛素化,参与胚胎发育、细胞周期调控和血压调节等生理过程。研究发现,Cul3功能失调后导致原癌蛋白积累或过度降解肿瘤抑制蛋白,与肿瘤密切相关。因此,本文将就泛素-蛋白酶体系统、E3泛素连接酶复合物,以及Cul3介导底物蛋白降解从而促进或抑制肿瘤的发生、发展作综述。     

非经典HLA—I类分子HLA—G在肿瘤免疫逃逸中的作用

HLA－G是非经典的HLA－I类基因，其编码产物的组织分布有限，主要分布在母胎组织的接触界面，在一些肿瘤中也有分布。多态性相对不明显，可通过与杀伤细胞抑制受体（KIR）结合，发挥抑制NK细胞和T细胞的效应。     

蛋白酶活化受体与肿瘤

蛋白酶活化受体（protease-activated receptors,PARs）是一类独特的具有7个跨膜区的G蛋白偶联受体（G protein-coupled recepor）,能够被特定的蛋白酶活化,进而通过其偶联的G蛋白调控相应的基因表达。在包括脉管、神经、胃肠、气管和皮肤等各种组织器官正常生理及病理状态下,PARs的表达会发生变化。近年研究表明在一些肿瘤组织中也存在PARs表达水平的变化,并且可以影响到肿瘤的发生、发展及侵袭和转移等肿瘤细胞的恶性生物学行为。对PARs与肿瘤的关系进行系统研究将丰富人们对肿瘤诊断治疗的相关知识,具有重要的意义。     

HLA-G蛋白在肿瘤组织及患者血清中的表达及其在肿瘤免疫逃逸中的作用

 随着对HLA-G蛋白作用机制的深入了解,越来越多的研究发现HLA-G与肿瘤免疫密切相关。大量研究显示在肿瘤患者的血浆、肿瘤组织中均可检测到HLA-G蛋白、mRNA的表达。     

HLA-G polymorphisms and HLA-G expression in sarcoidosis

BACKGROUND: The MHC class Ib molecule Human Leukocyte Antigen (HLA)-G may be important in induction and maintenance of immunological tolerance, and HLA-G expression may have a role in different cancers, in certain diseases with associations to HLA, and in organ transplantation. Sarcoidosis is a systemic granulomatous disease with unknown etiology but at the molecular level several studies have shown HLA associations. METHODS: In the present study, HLA-G alleles/polymorphisms were studied in sarcoidosis patients (n = 47) and controls (n = 129) by PCR techniques and HLA-G protein expression was investigated in granulomas from sarcoidosis patients with the use of immunohistochemistry. RESULTS: The HLA-G*010102/-G*0106 alleles were observed more often in sarcoidosis patients (39.4%) than in controls (26.4%), p = 0.025 (Fisher's exact test); however, not significant after correction (p(c) = 0.15). When HLA-G expression was investigated by immunohistochemistry in granulomas from sarcoidosis patients, weak HLA-G expression was observed in only one patient. CONCLUSIONS: HLA-G alleles that include a 14-bp sequence polymorphism in exon 8 of the HLA-G gene are observed more often in sarcoidosis patients than in controls. The sequence variation may influence HLA-G mRNA stability and influence the expression of soluble isoforms of HLA-G. Only rare and weak expression of HLA-G was observed in granulomas from sarcoidosis patients. More studies are needed to further elucidate the possible role for HLA-G in sarcoidosis.     

Functional role of human leukocyte antigen-G up-regulation in renal cell carcinoma

The nonclassical HLA-G molecule exhibits a limited tissue distribution and exerts multiple immune regulatory functions. Recent studies indicate that HLA-G expression plays a key role in the induction of immune tolerance and may represent a novel immune escape mechanism of tumor cells. Despite a high frequency of tumor-infiltrating T lymphocytes in renal cell carcinoma (RCC) lesions, outgrowth of tumor cells occurs that might be attributable to abrogation-efficient antitumor responses. To delineate the potential role of HLA-G in RCC immunology, the HLA-G expression pattern and its functional consequences on immune responses were analyzed in cell lines and lesions derived from primary RCC lesions. A heterogeneous constitutive and IFN-gamma-inducible HLA-G mRNA and protein expression was found in 12.5% of RCC cell lines but not in autologous normal kidney cells. Western blot analysis of 37 primary RCC lesions revealed HLA-G protein expression in 27% of RCC lesions. Functional studies performed with alloreactive natural and lymphokine-activated killer cells as well as antigen-specific CD8(+) T-cell populations demonstrated that HLA-G expression inhibits lysis of RCC cells by these different immune effector cells, whereas HLA-G(-) normal kidney cells were recognized. Furthermore, the HLA-G-mediated counteraction of immune response could be restored by antibody blocking experiments. Thus, aberrant HLA-G expression is found at a relatively high frequency in RCC and might participate in evasion of these tumor cells from immunosurveillance.     

Clinical and biological significance of HLA-G expression in ovarian cancer

Ovarian cancer is the most lethal gynecologic neoplastic disease in which the molecular etiology remains largely unclear. Like other cancer types, evolution of ovarian tumor cell species is accompanied by acquisition of novel gene products and these new tumor-associated antigens elicit a host immune response that creates selection pressure upon the emerging tumor clones. One of the mechanisms that ovarian cancer cells evade immune surveillance is by upregulating human leukocyte antigen-G (HLA-G) expression. HLA-G is a non-classical MHC class I molecule and accumulated evidence has suggested its biological role in inactivating immune response. It has been well known that HLA-G expression is frequently detected in the most aggressive type of ovarian cancer, i.e., high-grade serous carcinoma, and measurement of HLA-G protein levels has shown promise for detection and prognosis prediction in ovarian cancer. This review summarizes those recent studies on HLA-G expression in ovarian cancer with special focus on its clinical and biological significance which is fundamental to elucidate the molecular mechanisms in ovarian cancer development and paves the foundation for future HLA-G-based diagnostics and therapeutics.     

The role of HLA-G in gastrointestinal inflammatory disease and malignancy

Human leukocyte antigen (HLA)-G has been shown to act as an immune-inhibitory molecule and to interfere with the normal functions of natural killer (NK) cells and T-cells, conferring a potential route for HLA-G expressing cells to escape host immune surveillance. These findings have led to the rather intense study of HLA-G expression in several different arenas, including organ transplantation, inflammatory conditions, and in a wide variety of neoplasms including hematolymphoid neoplasms, visceral carcinomas, gliomas, and dermal-based neoplasms. This review will focus on the role of HLA-G in inflammatory conditions of the bowel, which can serve as an initiator of neoplastic alterations, as well as examine HLA-G expression and function in a variety of gastrointestinal malignancies. Although there are only a limited number of studies that have examined HLA-G in the gastrointestinal tract, the role of HLA-G has been controversial in this organ system with conflicting results reported even within the same tumor type.     

HLA-G在乳腺癌中的表达及意义

目的 探讨乳腺癌患者组织中人类白细胞抗原G(Human leukocyte antigen,HLA-G)的表达及其在乳腺癌诊断和预后中的作用。方法 分离纯化HLA-G蛋白,筛选出分泌抗HLA-G单克隆抗体的杂交瘤细胞株,得到抗HLA-G单克隆抗体。用免疫组织化学方法检测235例乳腺癌患者组织中HLA-G的表达,分析HLA-G的表达与各项临床病理指标、宿主免疫反应及生存率之间的关系。结果 HLA-G在乳腺癌患者的表达率为66%(155/235),HLA-G表达与肿瘤大小、临床TNM分期以及淋巴结转移有关。HLA-G阴性病人的生存率明显高于HLA-G阳性病人。结论 乳腺癌组织中HLA-G有较高表达,HLA-G的表达与宿主免疫反应及乳腺癌的预后有关,HLA-G的表达可能是影响乳腺癌病人预后的独立因素。