肝癌的CIK细胞免疫治疗研究进展

肝癌在全球肿瘤相关疾病中的死因占第二位,常规方法对其治疗效果并不理想,因此急需寻找新的有效方法来治疗。细胞因子激活的杀伤细胞是一种新型的免疫效应细胞,对肿瘤细胞的杀伤具有T淋巴细胞的高效性和NK细胞的非MHC限制性的特点,是目前对肝癌过继免疫治疗的有效方法之一。本文从细胞因子激活的杀伤细胞的扩增培养方法及研究进展、不同细胞因子及作用途径对其活性的影响、在杀伤肿瘤细胞中的作用机理及在肝癌治疗的实验研究与临床应用等方面进行了综述。     

肝细胞癌过继细胞免疫治疗研究进展

我国肝癌患者的病死率正在不断上升,严重威胁着人类的健康,因此急需探索出更多有效的治疗方法以延长患者的生存时间。肝脏由于其特殊的生理结构特点而发挥着免疫调节功能,基于此,肝癌的免疫治疗逐渐表现出了其临床优势,成为继手术、化疗、放疗后第四种肝癌治疗方法。过继细胞免疫疗法近几年在肝细胞癌的治疗中发展迅速。用于过继细胞免疫治疗的免疫细胞有CIK、NK、DC-CIK、TIL、CAR-T细胞,简单概述了这几种过继免疫细胞在肝细胞癌治疗中的研究现状及临床进展。     

肿瘤的过继性免疫治疗

生物治疗是当今肿瘤治疗四大模式之一，而其最主要体现是过继性免疫治疗（ＡＩＴ）的研究和广泛开展。ＡＩＴ常用的几种细胞有ＣＴＬ、ＬＡＫ、ＴＩＬ、ＣＤ３ＡＫ和ＴＤＬＮ细胞等。本文对以上几种细胞在过继性免疫治疗方面的特征和应用分别加以综述。     

人类白细胞E抗原和G抗原在HIV感染中的作用（二）

HLA基因型和细胞毒性T细胞 HLA抗原通过在与CTL相互作用的细胞表面上形成抗原一呈递结合物来刺激细胞应答，介导它们抑制受感染细胞并通过表面分子的杀伤细胞免疫球蛋白样受体（KIR）家族相互作用来激活先天免疫应答的自然杀伤（NK）细胞。重要证据表明，免疫应答可有效地削减HIV疾病的感染和传播。[第一段]     

滤泡辅助T淋巴细胞与HIV感染

滤泡辅助T淋巴细胞(T follicular helper cells,Tfh)是宿主正常体液免疫应答中的重要组成部分,为抗原特异性B细胞提供了关键的辅助作用。近年的研究发现,HIV感染可导致Tfh细胞的数量和功能异常,并可能与慢性HIV感染中体液免疫的异常、中和性抗体的产生及疫苗的免疫效果相关。本文对近年来有关Tfh细胞的研究进展进行综述,以期更好地理解HIV感染的致病机制。     

IL-21在HIV感染中作用的研究进展

白介素-21(IL-21)作为参与固有免疫和获得性免疫的多效性细胞因子,在机体的组织和细胞中分布广泛,对多种细胞的免疫调节功能起重要作用。IL-21主要来源于CD4~+T淋巴细胞,感染艾滋病病毒(HIV)后IL-21会显著降低,抗反转录病毒治疗后可部分恢复;低水平的IL-21在维持和调节HIV感染者的T细胞、自然杀伤细胞及B细胞的免疫应答中均发挥一定的调节作用,因此,IL-21可能是HIV的感染及疾病进展过程中非常重要的生物标志物。文章就IL-21在HIV感染中的作用作以下综述。     

基于NK细胞的免疫治疗在肝癌中的研究进展

自然杀伤细胞(NK细胞)是人体重要的免疫细胞，也是肝内主要的淋巴细胞，被认为是抵御肿瘤的第一道防线，对肝癌发生发展有重大影响。NK细胞所具有的特性，使其成为免疫治疗的新选择，基于NK细胞的免疫疗法或将在肝癌治疗中取得成功。本文就NK细胞的生物学特征、其在肝癌发生发展中的作用及相关治疗中的研究进展进行综述。     

HIV感染人群的NK细胞表型及功能变化

艾滋病病毒(HIV)作为艾滋病(AIDS)的病原体可损害人体免疫系统,使机体免疫功能部分或完全丧失,继而发生机会性感染、恶性肿瘤等严重并发症。HIV是当今世界最为严重的公共卫生问题之一。自然杀伤细胞(NK)是机体固有免疫系统中一种重要的细胞毒效应细胞,在机体抗感染和抗肿瘤免疫中发挥着重要作用;该细胞还具有良好的抗病毒及诱导、调节机体适应性免疫的作用。文章就NK细胞的表型及功能对HIV疾病的影响进行综述。     

IL-12与疟疾

IL-12是一种具有多种生物学活性的免疫效应细胞生长刺激因子。初步研究表明,它通过诱导和调节T细胞、NK细胞及其它细胞产生IFN-γ、TNF-α等细胞因子以诱生NO杀伤疟原虫。IL-12有望成为疟疾的治疗和预防药物,尤其是作为增强免疫应答的疫苗的佐剂,在抗疟原虫感染中起着重要的免疫保护作用。     

CAR-NK细胞治疗血液肿瘤的研究进展

NK细胞作为固有免疫细胞在肿瘤免疫监视中发挥重要作用。相比CAR-T其神经毒性、细胞因子释放综合征等不良反应和移植物抗宿主病鲜有发生，因此有希望成为嵌合抗原受体细胞免疫治疗更好的细胞来源。目前CAR-NK细胞的研究仍多使用根据T细胞激活原理设计的CAR。该文针对NK细胞激活原理设计的CAR结构、可用于免疫治疗的NK细胞来源和CAR-NK细胞在白血病、淋巴瘤、骨髓瘤的临床前景及临床研究进展进行综述。分析得出，“现货型”CAR-NK细胞将是血液肿瘤治疗的新方向，如何增加CAR-NK细胞在体内的存活时间仍是其应用于临床亟须解决的问题。     

NK cells: immune cross-talk and therapeutic implications

Increased evidence of cross-talk between NK cells and other immune cells has enhanced the possibilities of exploiting the interplay between the activation and inhibition of NK cells for immunotherapeutic purposes. The battery of receptors possessed by NK cells help them to efficiently detect aberrant and infected cells and embark on the signaling pathways necessary to eliminate them. Endogenous expansion of NK cells and their effector mechanisms are under exploration for enhancing adoptive immunotherapy prospects in combination with immunostimulatory and cell-death-sensitizing treatments against cancer, viral infections and other pathophysiological autoimmune conditions. Various modes of NK cell manipulation are being undertaken to overcome issues such as relapse and graft rejections associated with adoptive immunotherapy. While tracing the remarkable properties of NK cells and the major developments in this field, we highlight the role of immune cooperativity in the betterment of current immunotherapeutic approaches.     

Use of allogeneic NK cells for cancer immunotherapy

Controversy exists as to the role that the immune system plays in cancer therapy. While the immune system has been proposed to scavenge the body to prevent microscopic transformation from forming cancer, it has been difficult to mount its potential of shrinking established tumors. NK cells are components of the innate immune system. They can recognize targets without prior sensitization, making them ideal candidates to manipulate for therapeutic use against cancer. Initially, autologous NK cells were directed against tumors but it was realized that NK cells that recognize self cells are inhibited. More encouraging advances have been made with allogeneic NK cell therapy in clinical trials to overcome this limitation. In this article, we present developments in NK cell adoptive immunotherapy for hematologic and solid tumor malignancies.     

Natural killer cell function in women at high risk for HIV acquisition: insights from a microbicide trial

OBJECTIVE:: To assess the role of natural killer (NK) cells in HIV acquisition. DESIGN:: We conducted a nested case-control substudy to the Center for the AIDS Programme of Research in South Africa (CAPRISA004) tenofovir gel trial. METHODS:: Thirty women who acquired HIV infection (cases) and 30 women with high-risk sexual activity who remained HIV-negative (controls) were selected. Proliferation, degranulation and interferon-γ (IFNγ) secretion were measured by multiparametric flow cytometry after culture of recombinant human interleukin-2 (rhIL-2)-activated peripheral blood mononuclear cells with 721.221 cells or in-vitro HIV-infected, autologous CD4 T-cell blasts. Relationships between pre-acquisition NK cell responses and HIV acquisition were modeled with logistic regression models. RESULTS:: NK cells from cases had lower IFNγ responses to human leukocyte antigen-deficient 721.221 cells than controls (median %IFNγposNK cells: 13.7 vs. 21.6%, P?=?0.03). rhIL-2-activated NK cells from cases had responses to autologous HIV-infected target cells distinct from controls: cases had fewer proliferating and more frequent degranulating NK cells. NK cells from cases had significantly lower IFNγ responses to in-vitro HIV-infected autologous T cells than controls even after adjusting for responses to uninfected blasts (median %IFNγposNK-cells: 0.53 vs. 2.09%, P?=?0.007). Responses to in-vitro HIV-infected autologous T cells were significantly lower in herpes simplex virus 2 (HSV-2)-infected women (P?=?0.003). IFNγ NK cell responses to autologous HIV-infected cells were associated with lower risk of HIV acquisition (odds ratio adjusted for age, gel arm, HSV-2 and immune activation: 0.582, 95% confidence interval 0.347-0.977, P?=?0.04). CONCLUSION:: At the time of exposure to HIV, women with impaired NK cell IFNγ responses were more likely to acquire HIV infection. NK cells, as early responders to viral exposure, were associated with lower risk of HIV acquisition, independent of the intercalated effect of HSV-2 infection suppressing NK cell responses.     

Identification of the CD16low CD56low CD38pos Natural Killer Cell as a Key Subset in Patients with Multiple Myeloma

Background: Natural killer (NK) cells are classified as innate immune cells which can directly recognize and kill tumor cells without antigen sensitization. NK cell-based adoptive immunotherapy for blood malignancies has attracted more attention in recent years. Objective: To analyze different NK cell subsets in the peripheral blood and bone marrow (BM) of patients with multiple myeloma (MM). Methods: Using flow cytometry we analyzed: (i) the distribution of distinct NK cell subpopulations (i.e. CD16low CD56low, CD16pos CD56high, CD16neg CD56high, CD16high CD56low, CD16neg CD56low, CD16low CD56low CD38pos) in the BM from MM patients at distinct disease stages. (ii) the expression of NKG2D, DNAM-1 and NKp30, and (iii) the expression of CD107a in CD16low CD56low CD38pos and CD16low CD56low CD38neg NK cells subsets. Results: CD16low CD56low CD38pos was the dominant subset in BM from patients with MM at the CR stage with a decreased expression of NKp30. CD16low CD56low CD38pos subset showed a higher proportion of CD107a expression compared to CD16low CD56low CD38neg cells. In vitro experiments indicated that the CD16low CD56low CD38pos NK cell subset possesses more cytotoxicity than CD16low CD56low CD38neg NK cells. Conclusion: Our data suggest that CD16low CD56low CD38pos NK cells may reflect as an effector population with the potential therapeutic target in patients with MM. This group of cells may be useful for adoptive immunotherapy in MM in the future.     

The utility of ADCC responses in HIV infection

Simple antibodies or vector-induced T cell immunity are unable to provide broad immunity to HIV. Although broadly reactive neutralising antibodies are a goal of vaccination, this remains elusive. There is growing evidence that HIV-specific antibodies that mediate their activity via the Fc-receptor, such as antibody dependent cellular cytotoxicity (ADCC), have an important role in controlling HIV infection. Newer assays are being developed that enable HIV-specific ADCC responses to be finely mapped. In turn, this should allow a more definitive analysis of the effectiveness of HIV-specific ADCC antibodies. However, progressive dysfunction of effector cells that mediate ADCC responses, such as NK cells, combined with immune escape variants that emerge from effective ADCC responses, likely undermine the utility of ADCC responses during chronic HIV infection. Nonetheless the utility of ADCC responses in preventing HIV infection requires urgent consideration.     

Expansion of defective NK cells in early HIV type 1C infection: a consequence of reduced CD161 expression

Human immunodeficiency virus (HIV)-1 infection compromises the natural killer (NK) cell function and leads to defective control on virus multiplication. One of the major features of HIV-1 infection is the expansion of a functionally compromised defective NK cell subset (CD56(-)CD16(+)). We analyzed the NK cell subsets in early HIV infection to determine the effect of NK cell perturbation on the viral load set point, a marker of disease progression. We report that the defective NK cells are expanded in early HIV infection within 6-8 months of acquiring infection and are correlated with a higher plasma viral load set point, suggesting its utility as a predictive marker for disease progression. The expression of CD161, a molecular marker responsible for proliferation and differentiation of NK cells, was significantly down-regulated in the defective NK cells as compared to slow progressors (p=0.0009) and healthy controls (p=0.0003) and was correlated with a higher viral load set point in early HIV-1 infection (r=-0.6154, p=0.03), suggesting the probable role of CD161 expression in the impaired proliferation and differentiation of defective NK cells into the functional NK cells in early HIV infection. The reduction in CD161 expression on the defective NK cells in early HIV infection is thus indicative of the role of innate immune cells in early control of HIV infection.     

T-cell reconstitution and expansion after hematopoietic stem cell transplantation: 'T' it up!

Adoptive immunotherapy is the isolation and infusion of antigen-specific or nonspecific lymphocytes. Adoptive therapy with T cells may have a role in replacing, repairing, or enhancing immune function damaged by cytotoxic therapies, and rapid lymphocyte recovery may improve outcome after autologous and allogeneic stem cell transplantation (SCT). Recently, a plethora of information on the basic mechanisms of T-cell biology and regulation of cellular immune responses has emerged, permitting the development of new forms of adoptive cell therapy. Efficient ex vivo culture method for T-cell subsets affords the possibility of adoptive transfer of T cells engineered with enhanced capacity for central memory, effector cytotoxicity, Th1, Th2, veto cell, and T regulatory functions. Studies show that homeostatic T-cell proliferation is important for effective adoptive immunotherapy and pretreatment with chemotherapy may enhance the effects of infused T cells. Replicative senescence, in part due to telomere erosion, likely limits successful adoptive immunotherapy, though it may be possible to maintain T-cell pools by enforced expression of telomerase. Clinical trials now demonstrate that it is possible to enhance immune reconstitution after SCT with cytokines or infusions of ex vivo costimulated expanded T cells. These data all support the premise that adoptive therapy can accelerate reconstitution of cellular immunity with enhanced antitumor effects following SCT.     

Natural killer cells – new understanding of basic biology may lead to more effective allogeneic haematopoietic stem cell transplantation

The natural killer (NK) cells are part of the innate immune system and are responsible for initial defences in the surveillance against malignant cells and virally infected cells. In addition to direct cytotoxicity, cytokines produced by NK cells amplify the immune response and help control the neoplasm/pathogen. Several activating and inhibitory receptors responsible for NK cell activation are recently characterized and play a crucial role in tumour eradication. These include, but are not limited to, the killer immunoglobulin-like receptors, C-type lectin receptors and natural cytotoxicity receptors. The downstream signalling of some of these receptors is also characterized. The net balance in the sum of the signals generated by ligation of activating and inhibitory receptors determines the final outcome, cytotoxicity versus tolerance. NK cell-based immunotherapy can be successfully exploited in the haematopoietic stem cell transplantation for the treatment of haematological malignancies and has a potential to separate the beneficial graft versus leukaemia effect from, often dangerous, graft versus host disease. This article reviews the NK receptors important in NK-mediated cytotoxicity in allogeneic haematopoietic stem cell transplantation.     

Depletion of Tregs for adoptive T-cell therapy using CD44 and CD137 as selection markers

Several types of cancer have been shown to be susceptible to cellular immune responses, leading to investigations using various forms of T cell-based, tumor-directed immunotherapy. One potential obstacle for the successful application of these therapies is the suppressive function of Tregs. Goldstein and colleagues evaluate a strategy to identify and remove Tregs from an adoptive T-cell therapy product generated by in vivo vaccination. They demonstrate that the depletion of Tregs characterized by CD44 and CD137 expression enhances antitumor immunity in their mouse model.     

Use of natural killer cells as immunotherapy for leukaemia

Natural killer (NK) cells potentially play a significant role in eradicating residual disease following allogeneic haematopoietic cell transplantation, and have been explored as tools for adoptive immunotherapy for chemotherapy-refractory patients. NK cell cytotoxicity is modulated by multiple activating and inhibitory receptors that maintain a balance between self-tolerance and providing surveillance against pathogens and malignant transformation. The functional characteristics of NK cells are dictated by the strength of inhibitory receptor signalling. Major histocompatibility complex (MHC)-specific inhibitory receptor acquisition occurs sequentially during NK cell development, and is determined by the nature of immunological reconstitution after allogeneic haematopoietic cell transplantation. Polymorphisms of inhibitory receptors [killer immunoglobulin-like receptors (KIRs)] and their ligands (MHC) contribute to interindividual variability. As a result, the functional NK cell repertoire of individual donors has variable potential for graft-vs-leukaemia reactions. Models predicting NK cell alloreactivity, including KIR ligand mismatch and missing KIR ligand strategies, are discussed as algorithms for optimal NK cell donor selection. Future modifications to improve NK cell adoptive immunotherapy by means of increasing target recognition and reducing inhibitory signalling are being explored.