肺癌患者外周血NKG2A和NKG2D表达及其临床意义的研究

目的:通过研究肺癌患者外周血中自然杀伤细胞(NK)表面抑制性受体NKG2A和活化性受体NKG2D表达,分析探讨NKG2A与NKG2D表达失衡与肿瘤免疫逃逸的关系及其临床意义.方法:采用流式细胞术检测101例肺癌患者(肺癌组)和81例健康对照者(对照组)外周血中NK细胞含量及其表面受体NKG2A、NKG2D表达情况,分析...     

肺癌患者外周血CD+8 自然杀伤T细胞表面受体NKG2D和NKG2A表达的临床意义

 【摘要】　目的　检测肺癌患者外周血CD+8 自然杀伤（NK）T细胞表面受体NKG2D和NKG2A的表达,探讨二者表达失衡与肺癌免疫逃逸的关系。方法　选择95例原发未治疗的肺癌患者,采用流式细胞术检测CD+8 NKT细胞表面受体NKG2D和NKG2A的表达,以50名健康人为对照。结果　肺癌组CD+8 NKT细胞NKG2D+表达率[（77.07±5.77）%]明显低于对照组[（84.13±4.49）%],差异有统计学意义（t＝8.14,P＜0.05）;在TNM分期中,Ⅰ～ⅢA、ⅢB、Ⅳ期患者CD+8 NKT细胞NKG2D+表达率依次为（81.07±5.02）%、（76.95±4.70）%、（72.80±5.16）%,差异有统计学意义（F＝18.74,P＜0.05）。肺癌组CD+8 NKT细胞NKG2A+表达率[（33.58±8.82）%]明显高于对照组[（25.31±8.38）%],差异有统计学意义（t＝-5.46,P＜0.05）;在TNM分期中,Ⅰ～ⅢA、ⅢB、Ⅳ期患者CD+8 NKT细胞NKG2A+的表达率依次为（25.10±6.93）%、（33.24±3.76）%、（43.64±6.10）%,差异有统计学意义（F＝75.73,P＜0.05）。结论　肺癌患者CD+8 NKT细胞表面NKG2A和NKG2D表达失衡可能抑制该细胞的杀伤功能,而这可能是肿瘤免疫逃逸的机制之一。     

食管癌患者外周血自然杀伤T 细胞及其表面受体NKG2A与NKG2D检测的临床意义

 【摘要】　目的　研究外周血中自然杀伤（NK）T细胞及其CD+8 NKT细胞亚群在食管癌患者与健康人中的表达水平及NKT细胞活性改变,探讨NKT细胞受体与临床病理分期的相关性及其临床意义。方法　采用流式细胞术分析53例食管癌患者及39名健康对照者外周血中NKT细胞及CD+8 NKT亚群,检测NKT细胞受体NKG2A和NKG2D的表达并结合临床病理因素作比较分析。结果　与健康对照组相比,食管癌患者外周血NKT细胞表达增加[（4.32±0.73）%,（5.97±1.29）%]（t＝3.562,P＜0.01）,NKT细胞表面NKG2D的表达水平降低[（17.56±5.92）%,（15.12±1.56）%]（t＝3.892,P＜0.05）,而NKG2A的表达水平升高[（4.02±1.41）%,（5.99±4.59）%]（t＝4.015,P＜0.05）,且其变化与食管癌的病情进展有关。结论　NKT细胞及其CD+8 NKT亚群在食管癌患者中表达增加,提示患者机体抗肿瘤效应的免疫反馈增强;NKT细胞表面活化性受体NKG2D表达减少与其表面抑制性受体NKG2A表达增加可能是致使NKT细胞活性降低及食管癌患者免疫逃逸的机制之一,且这种NKT细胞表面受体的变化和食管癌病情的发展有一定的相关性。     

肺癌患者调节性T细胞与NK细胞活化受体NKG2D的相关性及其临床意义

目的 分析肺癌患者外周血中CD+4 CDHi25 CDLo127调节性T细胞及自然杀伤细胞(NK细胞)活化受体NKG2D的表达水平之间的关系,探讨其在肿瘤免疫逃逸机制中的作用及临床意义.方法 选择70例肺癌患者,均经病理确诊.采用流式细胞术(FCM)检测患者外周血中CD+4 CDHi25 CDLo127调节性T细胞、NK细胞及NKG2D表达水平,并以50名健康人为对照.结果 肺癌患者外周血中CD+4 CDHi25 CDLo127调节性T细胞比例较健康对照组明显升高[(8.4±4.1)％与(6.7±1.7)％],差异有统计学意义(t=3.09,P＜0.05);肺癌组NK细胞比例与健康对照组比较[(15.6±8.3)％与(17.2±4.2)％],差异无统计学意义(t=-1.33,P＞0.05);肺癌组NKG2D较健康对照组明显降低[(83.3±4.9)％与(87.4±2.9)％],差异有统计学意义(t=3.16,P＜ 0.05).CD+4 CDHi25 CDLo127调节性T细胞与NKG2D呈负相关性(r=-0.302,P＜0.05).结论 在肺癌患者外周血中调节性T细胞可能通过下调NKG2D,参与肿瘤免疫逃逸机制,二者可作为评估肺癌患者免疫功能状态及预后的参考指标.     

NKG2D受体配体系统介导肿瘤免疫逃逸的研究进展

摘 要：NK细胞作为机体固有免疫的重要组成部分，在肿瘤免疫监视机制中起重要作用。NKG2D是NK细胞重要的激活受体，通过识别位于肿瘤细胞表面的NKG2D配体，介导细胞毒效应清除肿瘤细胞。然而存在多种因素可影响NKG2D受体与配体的表达，阻断了NKG2D信号转导，为肿瘤细胞免疫逃逸提供可能。NKG2D受体配体系统还可作为临床诊疗的靶点，为肿瘤患者诊断、治疗以及评估预后提供依据。本文就NKG2D受体配体系统介导的肿瘤细胞免疫逃逸的机制以及目前已有的针对性免疫治疗方法进行综述，为临床应用提供更多思路。     

NKG2D/NKG2DL轴与肿瘤免疫治疗

自然杀伤（NK）细胞是固有免疫系统中发挥细胞毒性作用的淋巴细胞，而NKG2D是NK细胞最重要的活化性受体之一，它通过识别靶细胞表面的配体NKG2DL来传递活化信号并激活免疫细胞对靶细胞发挥杀伤作用，在肿瘤免疫治疗中发挥重要作用。肿瘤微环境（TME）内存在多种机制调节NKG2D和NKG2DL的表达，从而影响免疫系统对肿瘤细胞的清除并导致肿瘤逃逸。NKG2D的强激活作用及其配体NKG2DL在肿瘤细胞上的选择性表达，使NKG2D/NKG2DL轴成为肿瘤免疫治疗的潜在靶点。本文围绕NKG2D/NKG2DL 轴介导的免疫监视与逃逸的双重作用，揭示重塑TME 对肿瘤免疫的重要性；并就干预NKG2D/NKG2DL轴在肿瘤免疫治疗中的研究进展进行综述，为基于NKG2D/NKG2DL开发免疫治疗药物提供可靠依据和新思路。     

依赖NKG2D的肿瘤免疫逃避

活化性受体NKG2D（natural—killer group 2,member D）和其配基在NK、γδ^＋T和CD8^＋T细胞介导的肿瘤免疫应答中扮演了重要角色。NKG2D识别肿瘤细胞表面的配体激活效应细胞,产生有效的抗肿瘤免疫应答。但是在完全具有免疫能力的机体内,表达NKG2D配基的肿瘤仍能够生长发育,因此,在患肿瘤小鼠和肿瘤病人中一定存在着依赖NKG2D的免疫逃避机制。本文就依赖于NKG2D的免疫逃避作一详细综述,主要包括：干涉NKG2D受体的免疫逃避、干涉NKG2D配基的免疫逃避、细胞因子破坏NKG2D受体和配基的免疫逃避、抑制性细胞参与NKG2D介导的免疫逃避。这些研究为抗肿瘤治疗提供了新的途径。     

NK细胞活化受体NKG2D及sMICA在晚期肺癌免疫监视中的作用

背景与目的 NK细胞活化受体NKG2D及sMICA是近来肿瘤研究领域热点之一.本研究旨在观察晚期肺癌患者外周血中NK细胞受体NKG2D及sMICA表达水平的变化,并探讨它们在晚期肺癌免疫监控中的作用及其临床意义.方法 采用流式细胞术榆测115例肺癌患者外周血NK细胞受体NKG2D、T淋巴细胞哑群及NK细胞百分比,采用酶联免疫吸附反应检测肺癌患者外周血sMICA值,并以50例健康人作为对照.结果 晚期肺癌患者外周血sMICA、CD8+T细胞、NK细胞数量较对照组明显升高,而NK细胞受体NKG2D、CD3+T细胞、CD4+>T细胞、CD4+T/CD8+T值较对照组下降.NK细胞受体NKG2D和sMICA呈负相关(r=-0.319,P<0.05).NK细胞受体NKG2D与CD4+T细胞、CD4+T/CD8+T成正相关(P0.05),与CD8+T细胞成负相关(P<0.05);sMICA与CD4+T细胞、CD4+T/CD8+T成负相关(P<0.05),与CD8+T细胞成正相关(P<0.05);它们与CD3+T、NK细胞均无相关性(P>0.05).结论 外周血sMICA上调介导NK细胞活化受体NKG2D下调机制参与了晚期肺癌以肿瘤为中心抑制免疫网络的形成,它们可作为监视晚期肺癌患者免疫状态的参考指标,也可作为评估肺癌发生、发展的参考依据.     

人恶性肿瘤中NKG2D受体配体的表达在免疫调节中的作用

NKG2D(natural killer group 2 member D)受体及其配体是目前研究比较多的免疫学分子.NKG2D受体在与其配体结合后可以激活NK细胞和T细胞,杀伤有NKG2D受体配体表达的肿瘤细胞,因此NKG2D受体及其配体在肿瘤的免疫调节过程中有着重要作用.人类NKG2D受体的配体包括:主要组织相容性复合体I类相关蛋白(major histocompatibility complex class I-related protein,MIC)A和B以及UL.16结合蛋白(UL16 binding protein,ULBP).这些配体广泛表达于各种肿瘤表面,通过各种不同的机制对肿瘤免疫进行调节.     

食管癌患者自然杀伤细胞活化性受体NKG2D及其分泌性配体sMICA的检测

目的 探讨宿主自然杀伤(NK)细胞受体NKG2D在抗食管癌中的作用及其与肿瘤免疫逃逸的关系.方法 用流式细胞术检测50例食管癌、26名健康对照外周血NK细胞NKG2D的表达状况,用酶联免疫吸附(ELISA)法检测外周血中可溶性MHC-1类链相关分子A(sMICA)的含量表达.结果 食管癌患者手术前后及健康对照外周血NK细胞NKG2D的表达水平分别为(87.25±3.06)%、(88.38±4.24)%、(92.46±1.46)%,两组比较,差异有统计学意义(P<0.05).相应配体sMICA在食管癌患者血清中的表达较健康人中增高,但差异无统计学意义(P0.05);在食管癌患者中不同肿瘤大小、分化程度、手术分期及是否有淋巴结转移等中表达差异无统计学意义(P0.05);但在晚期患者(Ⅲ、Ⅳ期)和有淋巴结转移者中较健康对照明显增高,差异有统计学意义(P<0.05).结论 食管癌患者外周血NK细胞活性降低,其活化性受体NKG2D表达的下降是NK细胞活性下降的原因之一.食管癌患者免疫逃逸可能与NKG2D表达下凋及其配体sMICA的表达升高有关.     

NKG2D-vermittelte Lymphozytenaktivierung

A very important task of the immune system is the elimination of transformed cells in which both natural killer (NK) cells and cytotoxic T cells are critically involved. The activity of NK cells is the outcome of a finely tuned balance between stimulatory and inhibitory receptors on their surface. Recently, much progress has been made in understanding the structure and function of one of the stimulatory receptors, NKG2D. Both NK and cytotoxic T cells can be activated via NKG2D, and NKG2D ligands were found on the surface of multiple malignant tumor cells. This review focuses on the biology and importance in antitumor responses of NKG2D and its ligands.     

NKG2D ligands in tumor immunity

The activating receptor NKG2D (natural-killer group 2, member D) and its ligands play an important role in the NK, gammadelta(+) and CD8(+) T-cell-mediated immune response to tumors. Ligands for NKG2D are rarely detectable on the surface of healthy cells and tissues, but are frequently expressed by tumor cell lines and in tumor tissues. It is evident that the expression levels of these ligands on target cells have to be tightly regulated to allow immune cell activation against tumors, but at the same time avoid destruction of healthy tissues. Importantly, it was recently discovered that another safeguard mechanism controlling activation via the receptor NKG2D exists. It was shown that NKG2D signaling is coupled to the IL-15 receptor pathway in a cell-specific manner suggesting that priming of NKG2D-mediated activation depends on the cellular microenvironment and the distinct cellular context. This review will provide a broad overview of our up-to-date knowledge of the NKG2D receptor and its ligands in the context of tumor immunology. Strategies to amplify NKG2D-mediated antitumor responses and counteract tumor immune escape mechanisms will be discussed.     

依赖NKG2D的肿瘤免疫逃避

活化性受体NKG2D(natural-killer group 2,member D)和其配基在NK、γδ+T和CD8+T细胞介导的肿瘤免疫应答中扮演了重要角色.NKG2D识别肿瘤细胞表面的配体激活效应细胞,产生有效的抗肿瘤免疫应答.但是在完全具有免疫能力的机体内,表达NKG2D配基的肿瘤仍能够生长发育,因此,在患肿瘤小鼠和肿瘤病人中一定存在着依赖NKG2D的免疫逃避机制.本文就依赖于NKG2D的免疫逃避作一详细综述,主要包括:干涉NKG2D受体的免疫逃避、干涉NKG2D配基的免疫逃避、细胞因子破坏NKG2D受体和配基的免疫逃避、抑制性细胞参与NKG2D介导的免疫逃避.这些研究为抗肿瘤治疗提供了新的途径.     

NKG2D signaling in cancer immunosurveillance

The immune system is able to detect and eliminate transformed cells. The activating receptor NKG2D is particularly relevant for cancer immunosurveillance. NKG2D ligand expression renders tumor cells more susceptible to be killed by NK and T cells, and correlates with the clinical outcome of the disease. However, tumors develop mechanisms to overcome the NKG2D‐mediated immune response, which has been associated with poor prognosis and impairment of the clinical benefits of immunotherapy in many human cancers. The highly specific pattern of expression displayed by the NKG2D ligands, mainly confined to tumor cells, together with the strong immune response triggered by this receptor clearly supports the idea that the NKG2D‐mediated pathway may be a powerful target for the treatment of cancer. This review draws together the most recent discoveries concerning the biology of the NKG2D signaling and their therapeutic relevance in the context of cancer.     

MICA/NKG2D-mediated immunogene therapy of experimental gliomas

The failure of conventional cancer therapy renders glioblastoma an attractive target for immunotherapy. Tumor cells expressing ligands of the activating immunoreceptor NKG2D stimulate tumor immunity mediated by natural killer (NK), gammadelta T, and CD8(+) T cells. We report that human glioma cells express the NKG2D ligands MICA, MICB, and members of the UL16-binding protein family constitutively. However, glioma cells resist NK cell cytolysis because of high MHC class I antigen expression. Plasmid-mediated or adenovirus-mediated overexpression of MICA in glioma cells enhances their sensitivity to NK and T-cell responses in vitro and markedly delays the growth of s.c. and intracerebral LN-229 human glioma cell xenografts in nude mice and of SMA-560 gliomas in syngeneic VMDk mice. Glioma cells forming progressive tumors after implantation of stably MICA-transfected human LN-229 cells lost MICA expression, indicating a strong selection against MICA expression in vivo. Rejection of MICA-expressing SMA-560 cells in VMDk mice resulted in protective immunity to a subsequent challenge with wild-type tumor cells. Finally, the growth of syngeneic intracerebral SMA-560 tumors is inhibited by peripheral vaccination with adenovirus-mediated, MICA-infected irradiated tumor cells, and vaccination results in immune cell activation in the NK and T-cell compartments in vivo. These data commend MICA immunogene therapy as a novel experimental treatment for human malignant gliomas.     

NKG2D ligand expression in pediatric brain tumors

Adult brain tumors establish an immunosuppressive tumor microenvironment as a modality of immune escape, with several immunotherapies designed to overcome this barrier. However, the relationship between tumor cells and immune cells in pediatric brain tumor patients is not as well-defined. In this study, we sought to determine whether the model of immune escape observed in adult brain tumors is reflected in patients with pediatric brain tumors by evaluating NKG2D ligand expression on tissue microarrays created from patients with a variety of childhood brain tumor diagnoses, and infiltration of Natural Killer and myeloid cells. We noted a disparity between mRNA and protein expression for the 8 known NKG2D ligands. Surprisingly, high-grade gliomas did not have increased NKG2D ligand expression compared to normal adjacent brain tissue, nor did they have significant myeloid or NK cell infiltration. These data suggest that pediatric brain tumors have reduced NK cell-mediated immune surveillance, and a less immunosuppressive tumor microenvironment as compared to their adult counterparts. These data indicate that therapies aimed to improve NK cell trafficking and functions in pediatric brain tumors may have a greater impact on anti-tumor immune responses and patient survival, with fewer obstacles to overcome.     

NKG2D及其配体与肿瘤免疫治疗研究新进展

NKG2D为自然杀伤(NK)细胞表面的C型凝集素样活化性受体,NKG2D与肿瘤细胞表面配体结合,杀伤肿瘤细胞,但在肿瘤患者和患肿瘤小鼠体内存在着依赖NKG2D的免疫逃避机制.近年来利用各种分子生物技术调节受体和配体的表达来避免免疫逃避.