NKT细胞的生物特性及其在抗肿瘤免疫中的作用

[摘要] NKT细胞是一类特殊的T 淋巴细胞亚群,既表达NK 细胞受体,也表达T 细胞的相关受体。NKT细胞在多种免疫应答的调节中发挥重要作用,包括感染、自身免疫性疾病、代谢性疾病和癌症,其通过连接固有免疫系统和适应性免疫系统显示出强大的抗肿瘤活性。NKT细胞不仅能杀伤肿瘤细胞,也可激活其他抗肿瘤免疫细胞间接地发挥抗肿瘤作用,还能在肿瘤微环境中激活衰竭的免疫细胞,在抗肿瘤免疫中发挥重要的作用。本文就NKT细胞的生物学特性及其在抗肿瘤免疫中的作用作一综述。     

NKT细胞的生物特性及其在多发性骨髓瘤中应用的研究进展

NKT细胞是一种特殊的T淋巴细胞亚群,其表面既有T细胞受体,又有NK细胞受体。NKT细胞在肿瘤、自身免疫性疾病和微生物感染中起到调节免疫应答的作用,是联系固有免疫和获得性免疫的“桥梁”之一。多发性骨髓瘤（multiple myeloma,MM）是一种浆细胞异常增殖的恶性血液系统疾病。MM细胞表达CD1d分子并且可被具有CD1d限制性的NKT细胞杀伤。近些年,NKT细胞的抗MM作用成为研究热点,本文就NKT细胞生物特性及其在MM治疗中的应用进行综述。      

NKT细胞对肝癌免疫应答的双向调控作用

自然杀伤T(Natural killer T,NKT)细胞是一种特殊的T淋巴细胞亚群,也是肝脏内的天然免疫淋巴细胞,可分泌大量的细胞因子参与肝癌免疫调节,在肝癌的发生、发展和转移等免疫应答中发挥双重调控作用。其促肿瘤和抗肿瘤的双重调节功能与多种因素相关,本文对近年来NKT细胞对肝癌免疫的双向调控作用机制的研究进展进行总结。     

食管鳞癌患者手术前后外周血T细胞亚群与NK、NKT细胞检测的临床意义

目的:分析食管鳞癌患者手术前后外周血中T淋巴细胞亚群与NK、NKT细胞变化规律及其临床意义.方法:应用流式细胞术检测78例食管鳞癌患者外周血中T淋巴细胞亚群及NK、NKT细胞的水平.结果:肿瘤切除术前NKT细胞水平在中低分化组较高分化组显著下降(P<0.05);术后外周血中CD8+T细胞含量明显降低(P<0.01),CIM+/CD8+比值显著升高(P<0.01),同时NK与NKT细胞水平较术前显著下降(P<0.01).结论:手术可一定程度改善患者机体免疫功能,检查手术前后外周血T淋巴细胞亚群及NK、NKT细胞水平有助于患者的细胞免疫功能监测,为食管鳞癌临床治疗提供依据.     

食管鳞癌患者手术前后外周血T细胞亚群与NK、NKT细胞检测的临床意义

目的：分析食管鳞癌患者手术前后外周血中T淋巴细胞亚群与NK、NKT细胞变化规律及其临床意义.方法：应用流式细胞术检测78例食管鳞癌患者外周血中T淋巴细胞亚群及NK、NKT细胞的水平.结果：肿瘤切除术前NKT细胞水平在中低分化组较高分化组显著下降（P〈0.05）;术后外周血中CD8＋T细胞含量明显降低（P〈0.01）,CIM＋/CD8＋比值显著升高（P〈0.01）,同时NK与NKT细胞水平较术前显著下降（P〈0.01）.结论：手术可一定程度改善患者机体免疫功能,检查手术前后外周血T淋巴细胞亚群及NK、NKT细胞水平有助于患者的细胞免疫功能监测,为食管鳞癌临床治疗提供依据.     

CD3+CD56+NKT细胞及CD3-CD56+NK细胞在恶性肿瘤患者的临床意义研究

背景与目的细胞毒性淋巴细胞在抗肿瘤免疫效应中发挥着重要作用,CD3 CD56 NKT细胞作为一类新的具有细胞毒性的效应细胞,目前关于其抗肿瘤意义的探讨主要集中于血液系统恶性疾病,而在实体肿瘤中的应用和临床价值研究尚少。本研究旨在初步探讨抗肿瘤细胞CD3 CD56 NKT细胞及CD3-CD56 NK细胞在恶性肿瘤患者外周血的表达状态及其临床意义。方法采用流式细胞术分析118例恶性肿瘤患者(55例肺癌患者和63例乳腺癌患者)及46例健康对照组外周血中的T细胞亚群及CD3 CD56 NKT细胞、CD3-CD56 NK细胞表达。结果恶性肿瘤患者组CD3 CD8 T细胞、CD3 CD56 NKT细胞以及CD3-CD56 NK细胞表达率均明显高于健康对照组(P<0.01)。肺癌患者中以CD3 CD8 T细胞和CD3 CD56 NKT细胞明显增加为主;乳腺癌患者中以CD3 CD56 NKT细胞和CD3-CD56 NK细胞明显增加为主。结论CD3 CD56 NKT细胞在肺癌和乳腺癌患者的抗肿瘤效应中占据重要地位,而CD3 CD8 CTL和CD3-CD56 NK细胞在不同类型肿瘤患者中具有不同的重要性。     

T淋巴细胞在肿瘤免疫中的双重作用及其免疫治疗现状

摘 要：肿瘤免疫治疗作为一种新的手段取得了备受瞩目的临床疗效,在晚期肿瘤中甚至可以达到临床治愈。T细胞亚群作为机体细胞免疫功能的重要组成部分,在抗肿瘤免疫及肿瘤免疫逃避中均发挥着十分重要的作用。全文就T细胞亚群的生物学特性、在肿瘤免疫激活及肿瘤免疫逃避中的作用和机制及相关肿瘤免疫治疗研究进展作一综述。     

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。     

CD4+T细胞与肿瘤免疫

在肿瘤免疫中细胞免疫发挥着重要作用,其中T细胞介导的特异性免疫应答反应更为重要.近年来CD4+T细胞在抗肿瘤免疫中的作用越来越受到重视.在肿瘤免疫中CD4+T细胞启动后可以通过多种机制启动细胞毒性T淋巴细胞(CTL),维持和加强CTL的抗肿瘤反应,并且可以作为效应细胞发挥抗肿瘤作用,CD4+T细胞中的一个亚群细胞CD4+ CD25+T调节细胞对肿瘤免疫有抑制作用.     

CD4+T细胞与肿瘤免疫

在肿瘤免疫中细胞免疫发挥着重要作用,其中T细胞介导的特异性免疫应答反应更为重要.近年来CD4+T细胞在抗肿瘤免疫中的作用越来越受到重视.在肿瘤免疫中CD4+T细胞启动后可以通过多种机制启动细胞毒性T淋巴细胞(CTL),维持和加强CTL的抗肿瘤反应,并且可以作为效应细胞发挥抗肿瘤作用,CD4+T细胞中的一个亚群细胞CD4+ CD25+T调节细胞对肿瘤免疫有抑制作用.     

Human CD4+ CD25+ regulatory T cells suppress NKT cell functions

CD4+CD25+ regulatory T cells play an important role in peripheral tolerance. These cells have been reported to be capable of suppressing the response of CD4+CD25- T cells in vitro. The depletion of these cells evokes effective immune responses to tumor cells in vivo. In this study, we demonstrate that CD4+CD25+ T cells also suppress all subsets of Valpha24+NKT cells (Valpha24+CD4-CD8- double negative, Valpha24+CD4+, and Valpha24+CD8+) in both proliferation and cytokine production [IFN-gamma, interleukin-4 (IL-4), IL-13, and IL-10]. This suppression is mediated by cell-to-cell contact but not by a humoral factor or the inhibition of antigen-presenting cells. Moreover, the cytotoxic activity of Valpha24+NKT cells against some tumor cell lines is suppressed by CD4+CD25+ T cells. This finding is important in developing an effective immunotherapy for cancer.     

Peripheral blood IFN-gamma-secreting Valpha24+Vbeta11+ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load

Natural killer T (NKT) cells are CD1d-restricted lymphoid cells and are characterized by an invariant T-cell receptor, which in humans consists of a Valpha24 chain paired with a Vbeta11 chain. These cells are known for their rapid production of large amounts of cytokines (e.g., IFN-gamma and IL-4), thereby modulating other cells of the immune system such as T cells, NK cells and dendritic cells. NKT cells have been reported to play important regulatory roles in many immune responses, including antitumor immune responses. Here, we demonstrate an age-dependent decrease in circulating Valpha24(+)Vbeta11(+) NKT cell numbers in both healthy controls and cancer patients and demonstrate that in both groups females have higher NKT cell levels compared to males. In a large group of 120 cancer patients, we show that circulating Valpha24(+)Vbeta11(+) NKT cell numbers are about 50% lower than in age- and gender-matched healthy controls and that this decrease is independent of tumor type or tumor load. This decrease was not restored upon tumor removal by means of surgery or radiotherapy. Even though the percentage of NKT cells that secrete IFN-gamma, as detected by ELISPOT, is normal in cancer patients, the absolute number of circulating IFN-gamma-secreting NKT cells is reduced. Together, our results suggest that the reduced circulating Valpha24(+)Vbeta11(+) NKT cell numbers in cancer patients are not affected by tumor load, but might actually reflect a risk factor for tumor development, e.g., by hampering efficient tumor immunosurveillance.     

Inhibition of early tumor growth requires J alpha 18-positive (natural killer T) cells

The role of natural killer T (NKT) cells in the immune response to tumor cells has been largely unexplored. As a model of adoptive tumor immunotherapy, cells from the draining lymph nodes of mice immunized with a tumor-specific or irrelevant antigen were transferred to na?ve recipients with established tumor. Inhibition of early tumor growth (day 4) required the transfer of both CD8(+) and J alpha 18(+) (NKT) cells from immunized animals without regard to immunogen. In contrast, CD8(+) cells, but not J alpha 18(+) cells, were necessary for the inhibition of late tumor growth (day 8). Thus, the developing tumor changes in sensitivity to NKT-mediated events and the role for NKT cells cannot be replaced by the presence of tumor-specific cells during early tumor growth. This suggests that recruitment/activation of J alpha 18(+) NKT cells is an important consideration during the immune therapy of early stage tumors.     

The role of natural killer T cells in B cell malignancies

Little is known regarding the precise role of different subsets of natural killer T (NKT) cells in the immunopathogenesis of cancer diseases, particularly hematopoietic malignancies. Although it is well known that NKT cells counteract tumor immunity, conflicting reports on the role of NKT cells in hematopoietic malignancies support more investigations to clarify the interactions between NKT cells and the tumor. Among the hematopoietic malignancies, B cell malignancies derive from different stages of B cell maturation in which T cells play a pivotal role. There is evidence which implies the protective role of some subsets of NKT cells in solid cancers as well as B cell malignancies. In this review, we will discuss recent advances about the immunobiology of NKT cells and their precise role in the immunopathogenesis and treatment of different B cell malignancies.     

Natural killer T cell-mediated antitumor immune responses and their clinical applications

A unique lymphocyte population, CD1d-restricted NKT cells, has been revealed to be a key player in both the innate and acquired immune responses, including antitumor effects. Recent studies revealed that at least two subsets of CD1d-restricted NKT cells exist: type I, having invariant Valpha14 receptor; and type II, having heterogeneous non-Valpha14 receptor. The specific glycolipid ligand, alpha-GalCer, effectively stimulates mouse and human type I NKT cells. The activation of type I NKT cells substantially influences function of other various cell types, particularly DC, NK cells, CD4 Th1 cells, and CD8 cytotoxic T cells, all contributing to the antitumor immune responses. Recent studies also indicated that, unlike type I NKT cells, type II NKT cells have a potential to repress antitumor immune responses. In this review, we summarize the characteristics of the antitumor immune responses mediated by both mouse and human CD1d-restricted NKT cells and discuss their potential in clinical applications against cancer.     

食管癌患者外周血中自然杀伤性T细胞含量的检测及其临床意义

 　目的　研究食管癌患者外周血中自然杀伤性（NK）T细胞在手术前后的表达情况。方法　采用流式细胞术（FCM）分析59例食管癌患者手术前后外周血中CD3、CD56、CD4、CD8抗体的表达,研究NKT细胞及其亚群的表达情况及所占比例。结果　随着CD+3 CD+56 CD+8／CD+3 CD+56 CD+4的比值逐渐升高,Ⅲ～Ⅳ期食管癌患者的比例逐渐降低,ANOVA示组间差异有统计学意义（P＜0.05）;CD+3 CD+56 CD+8／CD+3 CD+56 CD+4的比值与CD+3 CD+56 CD+4 NKT细胞非线性相关;CD+3 CD+56 CD+8 NKT细胞与NK细胞正相关,与CD+3 T细胞负相关。结论　CD+3 CD+56 CD+8／CD+3 CD+56 CD+4 的比值可能与肿瘤负荷有关,并且有助于判断食管癌患者的疾病程度及预后。     

基于质谱流式细胞技术揭示TP53突变型乙型肝炎病毒相关性肝细胞癌的免疫微环境特征

目的 探讨TP53突变型乙型肝炎病毒（hepatitis B virus，HBV）相关性肝细胞癌（hepatocellular carcinoma，HCC）的肿瘤免疫微环境特征。方法 收集2018—2019年广西医科大学附属肿瘤医院肝胆外科手术切除的38例HCC患者活体组织标本及其配对癌旁组织标本，提取组织DNA，并进行基因突变分析。采用质谱流式细胞术（CyTOF）比较TP53突变组和TP53未突变组中癌组织与癌旁组织以及两组癌组织之间的免疫微环境特点。结果 采用CyTOF鉴定TP53突变组和TP53未突变组所有免疫细胞，结果鉴定为22个细胞亚群，包括CD4⁺T细胞亚群、CD8⁺T细胞亚群、B细胞亚群、树突细胞亚群、自然杀伤（natural killer cell，NK）细胞亚群、NKT细胞亚群、粒细胞亚群和2个未知细胞亚群。其中，TP53突变组癌组织中CD8⁺T细胞和CD4⁺T细胞的表达比例均较未突变组癌组织高（2.26% vs 0.47%，P=0.028；7.53% vs 3.55%，P=0.046）。结论 TP53突变型HBV相关性HCC的肿瘤免疫微环境具有免疫异质性。     

调节性T细胞与肿瘤

调节性T（regulatory T, Treg）细胞是一群具有抑制其他免疫细胞功能的负调控细胞，包括CD4+ Treg、CD8+ Treg、NKT Treg 和双阴性（double negative，DN）Treg细胞等四大类。研究显示，肿瘤微环境中Treg细胞数量升高，且这些升高的 Treg细胞能抑制抗肿瘤免疫、降低肿瘤免