基于HLA-E功能特点的肿瘤免疫治疗新策略

人类白细胞抗原-E（HLA-E）在多种肿瘤中呈高表达,其与肿瘤患者预后的关系呈现肿瘤类型依赖性。HLA-E主要通过与NK细胞或T细胞上的激活性（NKG2C）或抑制性（NKG2A）受体结合,在调控抗肿瘤免疫应答中发挥重要作用。基于此,靶向 HLA-E/NKG2A 以阻断 HLA-E 与 NKG2A 的相互作用或抑制 HLA-E 表达,有望成为增强抗肿瘤免疫应答的新策略。鉴于HLA-E的功能特点设计增强型或通用型的T/NK细胞过继免疫疗法,有望提高过继免疫细胞疗法的治疗效果,具有良好的研发和临床应用前景。如何将靶向HLA-E或NKG2A的疗法与其他免疫疗法有效联合,实现更精准的免疫治疗以提高临床治疗效果是目前该方面研发和应用需要解决的难题之一。     

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。     

T细胞免疫球蛋白黏蛋白分子-3 在肿瘤免疫中的作用和机制

应用单克隆抗体阻断PD-1、CTLA-4 等免疫检查点已在肿瘤免疫治疗中取得了一定成效,但尚有部分患者对免疫检查点阻断剂疗效不佳,其机制可能为存在其他抑制性旁路。T细胞免疫球蛋白黏蛋白分子-3(T cell immunolobulin and mucin-containing protein-3,TIM-3)是一种可表达于多种免疫细胞,并具有重要调控作用的免疫检查点分子。已有研究报道多种肿瘤外周血和肿瘤浸润性T细胞中存在TIM-3 高表达,并与预后不良相关。抗肿瘤免疫中,高表达TIM-3 的T细胞、DC及单核巨噬细胞,可抑制肿瘤免疫应答。临床前研究显示,抗TIM-3 单抗联合抗PD-1 单抗可发挥协同抗肿瘤效应。TIM-3 单克隆抗体已进入临床试验阶段。然而,TIM-3 在调控免疫细胞中的部分功能尚待阐明,进一步理解TIM-3 的免疫调节机制有助于推动基于阻断TIM-3 抗肿瘤免疫治疗的临床应用。     

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。     

靶向免疫检查点的肿瘤免疫治疗现状与趋势

针对免疫检查点的阻断是众多激活抗肿瘤免疫的有效策略之一。免疫检查点是指免疫系统中存在的一些抑制性信号通路,通过调节外周组织中免疫反应的持续性和强度避免组织损伤,并参与维持对于自身抗原的耐受。利用免疫检查点的抑制性信号通路抑制T细胞活性是肿瘤逃避免疫杀伤的重要机制。细胞毒性T淋巴细胞相关抗原-4（cytotoxic T lymphocyte-associated antigen-4,CTLA-4）抗体Ipilimumab是首个被美国FDA批准靶向免疫检查点的治疗药物,对其他的免疫检查点如程序性死亡蛋白-1（programmed death protein-1,PD-1）及其配体的抑制能够有效治疗多种肿瘤,而且能诱发持续的肿瘤缓解。靶向免疫检查点在抗肿瘤免疫治疗中有着广阔的应用前景,由于经典的化疗药物具有免疫调节作用,使得免疫治疗与化疗的联合成为新的趋势。      

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.     

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。     

自然杀伤细胞免疫检查点抑制剂在癌症治疗中的研究进展

近年来许多研究证实免疫检查点抑制剂在多种癌症治疗中的潜力。自然杀伤细胞（natural killer cell,NK）是固有免疫系统的重要组成部分,在肿瘤免疫监视中发挥重要作用。其作用效应依赖于其与抑制和（或）激动受体的结合,无需主要组织相容性复合体（major histocompatibility complex,MHC）便能有效杀伤肿瘤。NK细胞对实体和血液肿瘤有巨大的杀伤潜力,已被越来越多的研究证实是肿瘤免疫治疗的理想靶点。NK细胞上一些新发现的免疫检查点受体被证实在肿瘤微环境中介导NK细胞的功能障碍,是理想的肿瘤免疫治疗靶点。本文将重点论述近年来新发现的免疫检查点受体在调节NK细胞功能中的作用及其在肿瘤免疫治疗中的潜在应用。      

新型免疫检查点TIGIT在多发性骨髓瘤免疫治疗中的研究现状与应用前景

T细胞免疫球蛋白和免疫受体酪氨酸抑制性基序结构域(TIGIT)是近年新兴的免疫检查点蛋白, 研究表明TIGIT能够使免疫细胞功能障碍, 减弱抗肿瘤效应, 导致肿瘤免疫耐受与免疫逃逸。通过阻断TIGIT可以逆转免疫细胞衰竭, 发挥抗肿瘤效应, 有望成为新一代多发性骨髓瘤治疗靶点。     

NKG2D受体在抗肿瘤免疫中的作用

随着NK细胞活化型受体NKG2D及其配体的发现，人们对免疫效应细胞抗肿瘤作用的分子机制的认识有了显著进展，现综述NKG2D受体一配体的识别机制及其在抗肿瘤免疫中的作用。     

Cooperative therapeutic anti-tumor effect of IL-15 agonist ALT-803 and co-targeting soluble NKG2D ligand sMIC

Shedding of the human NKG2D ligand MIC (MHC class I-chain-related molecule) from tumor cell surfaces correlates with progression of many epithelial cancers. Shedding-derived soluble MIC (sMIC) enables tumor immune escape through multiple immune suppressive mechanisms, such as disturbing natural killer (NK) cell homeostatic maintenance, impairing NKG2D expression on NK cells and effector T cells, and facilitating the expansion of arginase I⁺ myeloid suppressor cells. Our recent study has demonstrated that sMIC is an effective cancer therapeutic target. Whether targeting tumor-derived sMIC would enhance current active immunotherapy is not known. Here, we determined the in vivo therapeutic effect of an antibody co-targeting sMIC with the immunostimulatory IL-15 superagonist complex, ALT-803, using genetically engineered transplantable syngeneic sMIC⁺ tumor models. We demonstrate that combined therapy of a nonblocking antibody neutralizing sMIC and ALT-803 improved the survival of animals bearing sMIC⁺ tumors in comparison to monotherapy. We further demonstrate that the enhanced therapeutic effect with combined therapy is through concurrent augmentation of NK and CD8 T cell anti-tumor responses. In particular, expression of activation-induced surface molecules and increased functional potential by cytokine secretion are improved greatly by the administration of combined therapy. Depletion of NK cells abolished the cooperative therapeutic effect. Our findings suggest that administration of the sMIC-neutralizing antibody can enhance the anti-tumor effects of ALT-803. With ALT-803 currently in clinical trials to treat progressive solid tumors, the majority of which are sMIC⁺, our findings provide a rationale for co-targeting sMIC to enhance the therapeutic efficacy of ALT-803 or other IL-15 agonists.     

NK细胞治疗多发性骨髓瘤的研究进展

多发性骨髓瘤（multiple myeloma,MM）是一种表达高水平HLA-E分子的血液系统常见的恶性肿瘤,其发病率占血液系统恶性疾病的第二位,至今仍无法治愈。HLA-E主要与自然杀伤细胞(natural killer cells,NK cells)表面的抑制性受体NKG2A相结合,起到抑制NK细胞杀伤功能的作用。从而使MM细胞逃逸NK细胞的免疫杀伤。而NK细胞具有强大的抗肿瘤作用以及良好的安全性,阻止HLA-E与NKG2A相互作用,恢复NK细胞的功能,可能对MM的治疗提供重大的帮助。本文将重点探讨NK细胞在治疗MM中的作用,包括恢复NK细胞自身功能以及过继性输注NK细胞的疗效。     

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 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.     

Human Leukocyte Antigen E Contributes to Protect Tumor Cells from Lysis by Natural Killer Cells

The nonclassic class I human leukocyte antigen E (HLA-E) molecule engages the inhibitory NKG2A receptor on several cytotoxic effectors, including natural killer (NK) cells. Its tissue distribution was claimed to be wider in normal than in neoplastic tissues, and surface HLA-E was undetectable in most tumor cell lines. Herein, these issues were reinvestigated taking advantage of HLA-E-specific antibodies, immunohistochemistry, and biochemical methods detecting intracellular and surface HLA-E regardless of conformation. Contrary to published evidence, HLA-E was detected in a few normal epithelia and in a large fraction (approximately 1/3) of solid tumors, including those derived from HLA-E-negative/low-normal counterparts. Remarkably, HLA-E was detected in 30 of 30 tumor cell lines representative of major lymphoid and nonlymphoid lineages, and in 11 of 11, it was surface-expressed, although in a conformation poorly reactive with commonly used antibodies. Coexpression of HLA-E and HLA class I ligand donors was not required for surface expression but was associated with NKG2A-mediated protection from lysis by the cytotoxic cell line NKL and polyclonal NK cells from healthy donors, as demonstrated by antibody-mediated relief of protection in 10% to 20% of the tested target-effector combinations. NKG2A-mediated protection of additional targets became evident on NK effector blocking with antibodies to activating receptors (DNAM-1, natural cytotoxicity receptors, and NKG2D). Thus, initial evidence that the long-elusive HLA-E molecule is enhanced by malignant transformation and is functional in tumor cells is presented here, although its importance and precise functional role remain to be addressed in the context of a general understanding of the NK ligand-receptor network.     

固有免疫细胞抗肿瘤免疫治疗的研究进展

固有免疫细胞（先天性免疫细胞）是机体对抗肿瘤的第一道防线,是肿瘤的免疫细胞治疗重要组成部分。细胞免疫治疗（CIT）是指通过向肿瘤患者输注经体外培养扩增或激活的具有抗肿瘤活性的免疫细胞,直接杀伤或激发机体免疫反应杀伤肿瘤细胞,达到治疗肿瘤的目的。这些细胞的种类有:细胞因子诱导的杀伤细胞、淋巴因子激活的杀伤细胞、肿瘤浸润淋巴细胞、树突状细胞、CD3e抗体激活的杀伤细胞及利用生物工程改造过的细胞毒性T细胞等。这些免疫细胞疗法在临床上得到了一定的应用,且通常和细胞因子联合使用,细胞因子结合回输的免疫细胞驱使机体的免疫细胞从数量和效率上得到加强,从而更加特异有效的杀伤肿瘤细胞。本文总结了执行固有免疫功能的T细胞（γδT细胞）、杀伤细胞（NK）、肿瘤-相关巨噬细胞(TAM)、树突状细胞（DC）及固有淋巴样细胞(ILC)在肿瘤免疫治疗中的研究及发展前景。     

The bispecific immunoligand ULBP2‐aCEA redirects natural killer cells to tumor cells and reveals potent anti‐tumor activity against colon carcinoma

NKG2D, an activating receptor expressed on NK cells and T cells, is critically involved in tumor immunosurveillance. In this study, we explored the potential therapeutic utility of the NKG2D ligand ULBP2 for the treatment of colon carcinoma. To this end we designed a fusion protein consisting of human ULBP2 and an antibody‐derived single chain targeting the tumor carcinoembryonic antigen (CEA). The bispecific recombinant fusion protein re‐directed NK cells towards malignant cells by binding to both, tumor cells and NK cells, and triggered NK cell‐mediated target cell killing in vitro. Moreover, tumor growth was significantly delayed in a syngeneic colon carcinoma mouse model in response to immunoligand treatment. The anti‐tumor activity could be attributed to the stimulation of immune cells with an elevated expression of the activation marker CD69 on NK, T and NKT cells and the infiltration of CD45+ immune cells into the solid tumor. In summary, it was demonstrated that immunoligands provide specific tumor targeting by NK cells and exert anti‐tumor activity in vitro and in vivo. This technology represents a novel immunotherapeutic strategy for solid tumors with the potential to be further developed for clinical applications.     

Interleukin-18 Synergism with Interleukin-2 in Cytotoxicity and NKG2D Expression of Human Natural Killer Cells

Natural killer (NK) cells play an important role in anti-tumor immunity. Interleukin (IL)-18 is animmunoregulatory cytokine that induces potent NK cell-dependent anti-tumor responses when administratedwith other cytokines. In this study, we explored the effects of combining IL-18 and IL-2 on NK cytotoxicity aswell as expression levels of the NK cell receptor NKG2D in vitro. Freshly isolated PBMCs were incubated for48 h with IL-18 and IL-2, then CD107a expression on CD3-CD56+ NK cells was determined by three-colour flowcytometry to evaluate the cytotoxicity of NK cells against human erythroleukemia K562 cells and human coloncarcinoma HT29 cells. Flow cytometric analysis was also employed to determine NKG2D expression on NK cells.The combined use of IL-18 and IL-2 significantly increased CD107a expression on NK cells compared with usingIL-18 or IL-2 alone, suggesting that the combination of these two cytokines exerted synergistic enhancement ofNK cytotoxicity. IL-18 also enhanced NKG2D expression on NK cells when administered with IL-2. In addition,blockade of NKG2D signaling with NKG2D-blocking antibody attenuated the up-regulatory effect of combiningIL-18 and IL-2 on NK cytolysis. Our data revealed that IL-18 synergized with IL-2 to dramatically enhance thecytolytic activity of human NK cells in a NKG2D-dependent manner. The results appear encouraging for theuse of combined IL-18 and IL-2 in tumor immunotherapy.     

髓源性抑制细胞联合免疫检查点抑制剂抗肿瘤治疗的研究进展CSCD

免疫检查点抑制剂(ICI)可通过恢复T细胞对肿瘤细胞的识别和损伤功能来增强原有的抗肿瘤免疫应答。ICI已被批准用于黑色素瘤、非小细胞肺癌(NSCLC)和肾细胞癌等多种肿瘤的治疗。然而,许多患者对免疫治疗没有反应。其中部分原因是由髓源性抑制细胞(MDSCs)介导的。这种异质的未成熟骨髓细胞群可以强烈抑制T细胞和NK细胞的抗肿瘤活性并刺激调节性T细胞(Treg)产生免疫抑制,导致肿瘤进展。MDSCs可以促进患者对免疫检查点抑制的耐药。越来越多的证据表明MDSCs在肿瘤患者中的比例和免疫抑制功能可用于治疗反应的预测。本综述重点介绍了MDSCs在免疫检查点抑制中的作用,并提供了MDSCs与ICI靶向联合治疗的策略,以提高后者在肿瘤治疗中的疗效。