CD47与淋巴瘤免疫治疗相关性的研究进展

CD47属于免疫球蛋白超家族成员,在人体多种细胞和组织上均有表达,但在肿瘤细胞上表达得更多,特别是在各种造血系统肿瘤中高表达。肿瘤细胞上表达的CD47与巨噬细胞上的信号调节蛋白α（SIRPα）结合抑制巨噬细胞对肿瘤的吞噬作用可导致肿瘤免疫逃逸。近年来CD47成为肿瘤研究的新热点,本文就CD47的结构与表达、CD47-SIRPα、靶向CD47抗体药物与淋巴瘤免疫治疗相关性研究作一综述。     

CD147及其与肿瘤关系的研究进展

CD14 7分子是一种广泛存在于人体各个组织器官的属于免疫球蛋白超家族的糖蛋白 ,参与机体多种生理过程。CD14 7已被证实在多种体内外肿瘤细胞中表达增加 ,其与肿瘤发展的关系是目前肿瘤细胞生物学研究领域的热点之一。目前认为CD14 7能刺激肿瘤细胞周围的纤维母细胞产生基质金属蛋白酶 ,从而促进肿瘤的浸润、转移。现综述CD14 7分子的结构、功能及其与肿瘤发展的关系。     

CD147及其与肿瘤关系的研究进展

CD147分子是一种广泛存在于人体各个组织器官的属于免疫球蛋白超家族的糖蛋白,参与机体多种生理过程.CD147已被证实在多种体内外肿瘤细胞中表达增加,其与肿瘤发展的关系是目前肿瘤细胞生物学研究领域的热点之一.目前认为CD147能刺激肿瘤细胞周围的纤维母细胞产生基质金属蛋白酶,从而促进肿瘤的浸润、转移.现综述CD147分子的结构、功能及其与肿瘤发展的关系.     

CDl47及其与肿瘤关系的研究进展

CDl47分子是一种广泛存在于人体各个组织器官的属于免疫球蛋白超家族的糖蛋白，参与机体多种生理过程。CDl47已被证实在多种体内外肿瘤细胞中表达增加，其与肿瘤发展的关系是目前肿瘤细胞生物学研究领域的热点之一。目前认为CDl47能刺激肿瘤细胞周围的纤维母细胞产生基质金属蛋白酶，从而促进肿瘤的浸润、转移。现综述CDl47分子的结构、功能及其与肿瘤发展的关系。     

靶向CD47 抗肿瘤治疗的研究进展

[摘要] CD47 是细胞表面高度糖化的穿膜蛋白，是一种“别吃我”信号，可与信号调节蛋白α（SIRPα）等形成CD47-SIRPα 抑制信号复合体，从固有免疫和适应性免疫两方面同时逃避机体的免疫监视。研究发现，CD47 在血液肿瘤和多种实体瘤中高表达，通过与巨噬细胞上的SIRPα 配体结合，启动一系列抑制性的信号转导而躲避吞噬，其高水平表达既能促进肿瘤细胞的生长又能促进肿瘤细胞的转移。通过抗CD47 抗体阻断CD47-SIRPα 信号通路，达到抑制肿瘤细胞的免疫逃逸，增强巨噬细胞的吞噬作用和适应性免疫应答，是免疫治疗肿瘤的新途径。目前，国内外开展了越来越多靶向CD47-SIRPα 的药物或抗体的基础研究和临床试验，有望从抗体分子设计和重组蛋白等方面解决靶向CD47 抗肿瘤治疗时发生的贫血和输液相关不良反应等问题。本文就CD47 的分子结构与生理功能、CD47-SIRPα 表达调控机制、CD47 抗肿瘤治疗研究现状以及靶向CD47 导致的相关生物安全性问题和解决方案等方面进行综述，为CD47新靶点的基础研究和临床应用提供参考。     

抗CD47靶向治疗研究现状及应用前景

在肿瘤发生发展过程中,肿瘤细胞逃逸了免疫系统的监视;免疫逃逸机制对于研发新的抗肿瘤治疗方案具有重要的意义。免疫治疗旨在激活患者自身的免疫系统,是肿瘤治疗相关研究的前沿,具有广阔的应用前景。CD47是一种广泛表达的细胞表面分子,肿瘤细胞可能借此“别吃我”信号,逃避了肿瘤免疫;肿瘤干细胞中CD47的表达水平甚至比肿瘤细胞更高。通过使用抗CD47抗体阻断CD47-SIRPα通路,从而介导细胞吞噬作用,能够靶向性杀伤肿瘤细胞。现在多项关于CD47靶向治疗的临床试验正在进行中,包括两种单克隆抗体和一种融合蛋白。然而由于使用动物模型不一,可能高估了这些药物的临床疗效预测。现将CD47抗肿瘤治疗相关研究的背景及潜在问题加以综述,并对该治疗的未来应用前景予以展望。      

CD147在肿瘤骨转移中作用的研究进展

CD147分子是一种广泛存在于人体各组织器官的属于免疫球蛋白超家族的糖蛋白,参与机体多种生理过程.CD147已被证实在多种体内外肿瘤细胞中表达增加,促进肿瘤的侵袭和转移,并促进肿瘤骨转移中破骨细胞的活化.其与肿瘤骨转移的关系是目前肿瘤细胞生物学研究领域的热点之一.     

补体调节蛋白CD59与肿瘤

作为补体终末阶段调节蛋白的CD59分子在多种实体瘤细胞表面高表达.高表达的CD59分子能够阻断补体激活途径降低补体系统对肿瘤细胞的溶解杀伤作用,最终导致肿瘤细胞逃避机体免疫监视.研究利用单克降抗体、细胞因子等抑制CD59的抗补体活性可在肿瘤免疫治疗中取得一定的疗效.     

CD47在胰腺癌组织中的表达及临床意义

目的 通过TCGA数据库及人类蛋白质谱数据库分析CD47表达、胰腺癌临床病理特征及患者总存活率之间的关系。通过GEPIA数据库进一步分析了CD47基因表达与免疫细胞浸润的关系。方法 在(TCGA)数据中初步筛选胰腺癌组织和癌旁正常组织中CD47的表达。应用蛋白质组学数据库(CPTAC)和人类蛋白质图谱数据库评估CD47蛋白的表达。应用(ROC)曲线评价CD47 mRNA表达对胰腺癌的诊断价值。采用多因素分析和Kaplan-Meier生存曲线分析CD47表达与临床病理参数和总生存期(OS)的关系。同时，使用GEPIA数据集探究CD47基因表达与免疫细胞浸润的关系。结果 胰腺癌组织中CD47表达明显高于癌旁正常组织。ROC曲线分析显示，以5.236为界值，CD47鉴别胰腺癌与癌旁对照的准确性、敏感性和特异性分别为97.0%、95.0%和91.8%。Kaplan-Meier生存分析显示，CD47高表达的胰腺癌患者预后比CD47低表达的患者差。单因素和多因素分析显示，CD47是胰腺癌患者的独立危险因素。相关分析表明，CD47的表达与肿瘤纯度和免疫浸润有关。结论 CD47表达缺失与胰腺癌的疾病进...     

抗CD47单克隆抗体制备及其促巨噬细胞吞噬作用鉴定

目的:制备可识别肿瘤细胞表达CD47蛋白的抗CD47单克隆抗体,并鉴定其抗肿瘤作用。方法:利用BL21(DE3)原核表达系统表达CD47胞外段蛋白,利用Ni-NTA层析纯化表达蛋白。免疫BALB/c小鼠,制备并筛选分泌抗CD47单克隆抗体的杂交瘤细胞株。利用正辛酸-硫酸铵沉淀方法纯化抗CD47单抗。利用流式细胞术检测纯化抗体的活性。利用巨噬细胞与肿瘤细胞共培养试验,检测抗CD47单抗的抗肿瘤作用。结果:表达并纯化了CD47胞外段蛋白,筛选到了分泌抗CD47单克隆抗体的杂交瘤细胞株—7D4,流式细胞术检测结果显示,抗体具有结合肿瘤细胞的活性,但是对不同肿瘤类型细胞的结合效率存在差异。巨噬细胞与肿瘤细胞共培养试验发现,利用抗体封闭肿瘤细胞CD47信号后,可以增强巨噬细胞对肿瘤细胞的吞噬作用。结论:抗CD47单抗—7D4可以促进巨噬细胞的吞噬作用,具有潜在应用价值。     

肿瘤坏死因子CD70在肿瘤发生与治疗中的研究进展

CD70是肿瘤坏死因子(TNF)超家族的成员之一，是一种Ⅱ型跨膜蛋白，在调控免疫应答过程中发挥重要的作用。CD70的高表达常见于多种肿瘤组织中，目前以CD70为靶点的免疫治疗药物已经在临床前期研究中应用。CD70在肿瘤细胞表面的表达，不仅可使肿瘤细胞逃避免疫监视、诱导免疫细胞凋亡，同时也可以激活部分免疫细胞杀伤肿瘤细胞，这些作用给恶性肿瘤的免疫治疗带来了新的方向。本文就近年来CD70在肿瘤研究中的进展作一综述。     

Identification of pancreatic cancer stem cells

Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Pancreatic cancer cells with the CD44(+)CD24(+)ESA(+) phenotype (0.2-0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44(+)CD24(+)ESA(+) cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. The enhanced ability of CD44(+)CD24(+)ESA(+) pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44(+)CD24(+)ESA(+) pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation.     

CD47‐signal regulatory protein α signaling system and its application to cancer immunotherapy

Tumor cells evade immune surveillance through direct or indirect interactions with various types of immune cell, with much recent attention being focused on modifying immune cell responses as the basis for the development of new cancer treatments. Signal regulatory protein α (SIRPα) and CD47 are both transmembrane proteins that interact with each other and constitute a cell‐cell communication system. SIRPα is particularly abundant in myeloid cells such as macrophages and dendritic cells, whereas CD47 is expressed ubiquitously and its expression level is elevated in cancer cells. Recent studies have shown that blockade of CD47‐SIRPα interaction enhances the phagocytic activity of phagocytes such as macrophages toward tumor cells in vitro as well as resulting in the efficient eradication of tumor cells in a variety of xenograft or syngeneic mouse models of cancer. Moreover, CD47 blockade has been shown to promote the stimulation of tumor‐specific cytotoxic T cells by macrophages or dendritic cells. Biological agents, such as Abs and recombinant proteins, that target human CD47 or SIRPα have been developed and are being tested in preclinical models of human cancer or in clinical trials with cancer patients. Preclinical studies have also suggested that CD47 or SIRPα blockade may have a synergistic antitumor effect in combination with immune checkpoint inhibitors that target the adaptive immune system. Targeting of the CD47‐SIRPα signaling system is thus a promising strategy for cancer treatment based on modulation of both innate and acquired immune responses to tumor cells.     

CD47: a potential immunotherapy target for eliminating cancer cells

The relationship between the immune system and cancer growth and aggravation has been discussed over a century. A number of molecules have been shown to participate in this process. CD47, a normal universally expressed member of the immunoglobulin superfamily, plays multiple functions in immune system. Researches demonstrated that CD47 was also highly expressed on the surface of tumor cells as well as cancer stem cells (CSCs). Whether the highly expressed CD47 was associated with tumor growth, metastasis, recurrence, or drug resistance has become the hotspot. Besides the roles of CD47 in tumor immunoregulation, the monoclonal antibodies targeting CD47 used in acute myelogenous leukemia (AML) and bladder CSCs were reported, which shed new light on tumor treatment. CSCs have been recognized as the root of tumor drug resistance and recurrence. Whether CD47 on CSCs could serve as a potential target for future anti-cancer treatment forms the focus of our review. Here we highlight the potential roles of CD47 in immune system, and discuss the promising therapeutic application of anti-CD47 antibodies for eliminating tumor cells.     

PD-1/PD-L1通路在乳腺癌治疗中的作用及意义

程序性死亡受体1（programmed death-1,PD-1,CD279）为共刺激受体CD28超家族成员,主要表达在活化T细胞、B细胞、单核细胞以及自然杀伤细胞表面。程序性死亡配体1（programmed death-ligand 1,PD-L1,CD274）为PD-1的一个重要配体,广泛表达于肿瘤细胞以及抗原呈递细胞（APC）表面。以PD-1/PD-L1为靶点的肿瘤免疫治疗为肿瘤治疗开辟了新的道路。PD-1通过与PD-L1和(或)PD-L2结合,抑制T细胞活化,诱导T细胞凋亡,在肿瘤免疫逃逸中起着重要的作用。目前PD-1/PD-L1信号通路成为免疫靶向治疗的新靶点,相关研究在非小细胞肺癌、晚期黑色素瘤等多种恶性肿瘤领域有重大进展,研究发现PD-L1 在多种肿瘤细胞包括乳腺癌中表达上调,提示 PD-1/PD-L1通路可能参与肿瘤的免疫逃逸。本文将针对PD-1/PD-L1通路在乳腺癌治疗中的作用及意义进行综述。     

Application of natural killer cells in pancreatic cancer

Pancreatic cancer, a highly malignant disease, is characterized by rapid progression and early metastasis. Although the integrative treatment of pancreatic cancer has made great progress, the prognosis of patients with advanced pancreatic cancer remains extremely poor. In recent years, with the advancements in tumor immunology, immunotherapy has become a promising remedy for pancreatic cancer. Natural killer (NK) cells are the key lymphocytes in the innate immune system. NK cell function does not require antigen pre-sensitization and is not major histocompatibility complex restricted. By targeting tumors or virus-infected cells, the cells play a key role in immune surveillance. Although several questions about NK cells in pancreatic cancer still need to be further studied, there are extensive theories supporting the clinical application prospects of NK cell immunotherapy in pancreatic cancer. Since very few studies have evaluated the role of NK cells in pancreatic cancer, this review provides a comprehensive update of the role of NK cells in pancreatic cancer immunotherapy.     

CD47基因mRNA在人恶性胸膜间皮瘤中的表达及意义

目的:分析CD47基因mRNA在MPM细胞和组织中的表达,并评价其与MPM患者临床病理特征及预后的关系。方法:采用RT-qPCR分析人正常胸膜间皮LP9细胞系和MPM细胞系NCI-H28（上皮样型）、NCI-H2052（肉瘤样型）、NCI-H2452（双相混合型）中CD47基因mRNA表达量;采用RT-qPCR检测12例MPM组织及配对正常胸膜组织中CD47基因mRNA表达量。通过Oncomine数据库对非瘤组织与MPM组织中CD47基因的表达差异进行分析。利用TCGA数据库对CD47基因mRNA表达量与MPM临床病理特征的相关性进行分析。构建Kaplan-Meier模型探讨CD47基因mRNA表达量对MPM患者预后的影响。利用cBioportal在线工具对CD47与MPM肿瘤标志物基因的表达进行相关性分析。结果:RT-qPCR检测和Oncomine数据库检索发现,与配对正常胸膜细胞和组织相比,MPM细胞和组织中CD47基因mRNA的表达量均呈现显著的增加（P＜0.01）。CD47基因表达量与MPM患者肿瘤类型相关（P＜0.05）。CD47基因表达量与MPM患者总生存率和无疾病进展生存率均无显著关联（Logrank P＞0.05）。Cox多因素分析表明,非上皮性型肿瘤是导致MPM患者预后不良的独立危险因素（P＜0.05）。CD47基因表达与EFEMP1、MSLN和CALB2基因的表达具有显著正相关（P＜0.01）。结论:CD47基因mRNA在MPM细胞和组织中均呈现显著增高,其表达量与MPM患者的肿瘤类型相关,但CD47基因mRNA表达量与MPM患者预后之间无显著关联。     

CD40 activation as potential tool in malignant neoplasms

BACKGROUND: CD40, a cell surface molecule, is expressed on B-cell malignancies and many different solid tumors. It is capable of mediating diverse biological phenomena such as the induction of apoptosis in tumors and stimulation of the immune response. It has thus been studied as a possible target for antitumor therapy. The general aim of this review is to focus the attention of clinical oncologists on the involvement of CD40 in tumors and the rationale of CD40-activation-based therapies in new, biologically oriented antitumor protocols. METHODS: A Medline review of published papers about the role of CD40 activation in cancer therapy. RESULTS: Many authors have shown that CD40 activation promotes apoptotic death of tumor cells and that the presence of the molecule on the surface of carcinoma lines is an important factor in the generation of tumor-specific T-cell responses that contribute to tumor cell elimination. The CD40 ligand (CD40L) is the natural ligand for CD40; it is expressed primarily on the surface of activated T lymphocytes. Preclinical studies suggest that CD40-CD40L interaction could be useful for cytotoxicity against CD40-expressing tumors and for immune stimulation. Tumor inhibition was observed when tumor cells were treated with agonistic anti-CD40 monoclonal antibodies or with the soluble form of CD40L. The results of the first phase I clinical trial to treat cancer patients with subcutaneous injection of recombinant human CD40L have been recently reported. Immunohistochemical studies have revealed that detection of CD40 in primary cutaneous malignant melanoma and lung cancer may have a negative prognostic value. Interestingly, up-regulation of CD40 was observed in the tumor vessels of renal carcinomas and Kaposi's sarcoma, suggesting possible involvement of CD40 in tumor angiogenesis. Recently, it has also been shown that CD40 engagement on endothelial cells induces in vitro tubule formation and expression of matrix metalloproteinases, two processes involved in the neovascularization and progression of tumors. CONCLUSIONS: CD40 activation represents an exciting target for hematological malignancies and solid tumors expressing the molecule, but its functional role in cancer development still remains unclear and controversial.     

Tumor doubling time and local immune response to hepatic metastases from colorectal cancer

BACKGROUND AND OBJECTIVES: A number of studies have investigated the role of tumor-infiltrating lymphocytes in cancer, yet the local immune response to hepatic colorectal cancer metastasis remains unclear. As the tumor doubling time (DT) of hepatic colorectal cancer metastases is a good index of tumor growth, we examined the correlation between tumor DT and the local immune response by phenotype in hepatic colorectal cancer metastases. METHODS: Tumor DT and local immune response were examined in 20 patients with hepatic colorectal cancer metastases by analyzing tumor-infiltrating lymphocytes using flow cytometry or immunohistochemical studies. Tumor proliferative activity was also investigated by determining the expression levels of Ki-67 and proliferating cell nuclear antigen (PCNA). RESULTS: Locally abundant populations of CD83(+) dendritic cells (DCs) and CD8(+) T cells were positively related to longer tumor DT (P < 0.05), as were abundant CD8(+) T cells having interferon-gamma-producing potentials (P < 0.05). There was no significant correlation between tumor cell expression levels of Ki-67 or PCNA and tumor DT. CONCLUSIONS: Longer DT tumors have increased local populations of CD8(+) T cells and CD83(+) DCs even in hepatic colorectal cancer metastases.