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。     

CD47与淋巴瘤相关性的研究进展

淋巴瘤的发生与发展是许多因素共同作用的结果，其中免疫系统在其发展中也发生着重要的作用。CD47是高表达于淋巴瘤细胞表面的糖化跨膜蛋白，它与其配体抑制性受体信号调节蛋白（ SIRPα）结合后可抑制巨噬细胞的吞噬作用，产生免疫逃逸，从而促进淋巴瘤的发生与发展。本文阐述了CD47的结构、生理功能及相关的表达调控，并对CD47在淋巴瘤的预后及治疗中的作用进行了综述。     

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。     

淋巴瘤微环境与免疫逃逸关系的研究进展

淋巴瘤微环境是影响淋巴瘤发生、发展的重要因素,参与调控机体免疫系统对淋巴瘤细胞的识别和免疫应答。在淋巴瘤的免疫治疗时代,微环境的状态也影响了基于单克隆抗体、小分子化合物等免疫靶向药物对淋巴瘤细胞的作用。其中,微环境相关的免疫逃逸是导致淋巴瘤治疗失败的重要因素之一。文章就基质细胞免疫细胞亚群、血管增生、缺氧状态、免疫检查点等微环境因素和免疫逃逸的相关研究最新进展进行综述。     

CD+4CD+25调节性T细胞与肿瘤免疫

 近期研究发现一个有独特免疫调节功能的T细胞亚群：CD+4 CD+25调节性T细胞,不仅能抑制自身免疫性疾病发生,还参与肿瘤免疫的调节。这群细胞具有免疫无能和免疫抑制特性,与肿瘤免疫逃逸有密切的关系。肿瘤环境中CD+4 CD+25调节性T细胞增加,导致肿瘤免疫失调,去除这群细胞可有效诱导肿瘤免疫,为肿瘤治疗提供了一种新的思路。     

CD47分子在弥漫大B细胞淋巴瘤肿瘤微环境中的研究进展

弥漫大B细胞淋巴瘤（DLBCL）是成年人常见的高度侵袭性恶性血液肿瘤。DLBCL为一种高度异质性淋巴瘤,患者在分子生物学特征、临床表现和预后方面均存在巨大差异。目前越来越多的证据表明,肿瘤微环境对DLBCL的发生、发展发挥着重要的作用。CD47分子是一种整合素相关蛋白,在DLBCL细胞中过度表达,并在淋巴瘤免疫逃逸中起关键作用。本文拟就CD47分子相关信号通路、在DLBCL肿瘤微环境中的作用和DLBCL中靶向CD47分子的治疗策略等方面的研究进展进行综述。     

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。      

BTLA在肿瘤免疫中的作用及其临床意义

继程序死亡分子（PD-1）与细胞毒性T细胞相关抗原-4（CTLA-4）之后,CD28家族的新成员B、T淋巴细胞弱化因子（BTLA）已成为新的研究热点。BTLA表达谱介于PD-1和CTLA-4之间,它不仅表达于T细胞,在B细胞、NK细胞、巨噬细胞和树突状细胞中也有表达。BTLA与其配体结合传递共抑制信号,在机体抗肿瘤免疫应答中发挥负性调节作用,并与肿瘤的免疫逃逸机制相关,可能成为肿瘤生物治疗潜在的靶点。     

程序性凋亡分子1及其配体信号通道对调节性T淋巴细胞及肿瘤细胞的影响

程序性凋亡分子-1(PD-1)及其配体(PD-L1)是抑制性共同刺激分子中的重要成员之一,在多种肿瘤细胞及其相关细胞表面高表达,而肿瘤浸润的T淋巴细胞中调节性T淋巴细胞(Treg)的比例也异常升高.PD-L1与PD-1结合和Treg帮助肿瘤逃避免疫清除减弱了免疫应答和诱导免疫耐受.最新研究发现,PD-L1分子是诱导型Treg(iTreg)发育和功能维持的重要分子,PD-L1信号可将初始CD4+ CD25-T细胞转化成iTreg,发挥免疫抑制作用.对PD-1信号通道的研究可为抑制肿瘤免疫逃逸临床应用中肿瘤的免疫治疗提供新的理论依据和更好的治疗方法.     

人淋巴瘤细胞Jurkat通过Fas/FasL途径抑制人肺癌细胞A549的免疫逃逸

背景与目的 当机体发生肿瘤时,肿瘤细胞可以多种方式逃避免疫系统的监控而分裂生长,这就是肿瘤的免疫逃逸.研究表明,肿瘤细胞自身凋亡减少以及机体免疫细胞凋亡增加是肿瘤免疫逃逸的重要机制.Fas/FasL系统是介导凋亡的重要分子体系,本研究旨在通过观察人淋巴瘤细胞株Jurkat诱导人肺癌细胞株A549凋亡过程中凋亡信号分子Fas、FasL及casPase-8表达的改变,从而探讨Fas/FasL途径在肺癌细胞免疫逃逸中的作用.方法 人肺癌细胞株A549与人淋巴瘤细胞株Jurkat以不同比例分别进行共同培养,采用台盼蓝拒染法检测两种细胞存活率;流式细胞术(flow cytometry,FCM)检测两种细胞的凋亡率;Western blot技术检测A549细胞中Fas、FasL及caspase-8蛋白表达水平.结果 随着Jurkat/A549细胞比例逐渐增大,A549细胞的凋亡率明显增加,Jurkat细胞凋亡率显著减少;同时A549细胞中Fas及casPase-8蛋白的表达水平明显上调,而对FasL蛋白的表达水平无明显影响.结论 Jurkat细胞可能通过Fas/FasL途径介导了人肺癌细胞株A549的凋亡,从而抑制了A549细胞的免疫逃逸.     

Lewis Y antigen modified CD47 is an independent risk factor for poor prognosis and promotes early ovarian cancer metastasis

CD47 is a membrane receptor that belongs to the immunoglobulin superfamily and plays an important role in the mechanisms of tumor immune escape. CD47 participates in tumor immune escape by combining with SIRPα to reduce the phagocytic activity of macrophages. There are six potential N-glycosylation sites on CD47, and glycosylation is known to be necessary for its membrane localization. However, it is still unknown to what extent glycosylation influences CD47 ligand binding properties and subsequent signaling. By using immunoprecipitation and confocal laser scanning microscopy, we showed that CD47 contains Lewis y antigen. Immunohistochemical analysis demonstrated that both the positive expression and the overexpression of CD47 and Lewis y antigen in cancer tissues and borderline tumors were significantly higher than those in benign ovarian tumors and normal ovarian tissues (P < 0.05). A linear correlation between the expression patterns of CD47 and Lewis y antigen was evident (r = 0.47, P < 0.01). The high expression of CD47 and Lewis y antigen showed significant correlations with the clinical pathological parameters of ovarian cancer [International Federation of Gynecology and Obstetrics (FIGO) standards, lymph node metastasis, and degree of differentiation] (P < 0.05). The Cox model and Kaplan-Meier tests showed that high expression of CD47 was an independent adverse risk factor for the prognosis of ovarian cancer. Cases with both high CD47 and Lewis y antigen expression had poor prognoses. Our study demonstrates that Lewis y antigens of CD47 may play a crucial role in the development of ovarian cancer, and could be new targets for immunotherapy for ovarian cancer.     

CD47与胰腺癌相关性的研究进展

CD47分子是一种高度糖化的跨膜蛋白,存在于所有组织的多种细胞表面上。近几年的研究表明,CD47分子与多种恶性肿瘤密切相关,在大部分肿瘤细胞中呈现高表达,它与特异性配体结合后,可对免疫细胞吞噬肿瘤细胞产生抑制作用,使其产生免疫逃逸,故可促进肿瘤的发生与发展。胰腺癌是常见的消化系统肿瘤,恶性程度极高,诊断、治疗困难,预后不理想。与其他肿瘤类似,胰腺肿瘤与人体免疫系统之间也存在一定相关性,但CD47与胰腺癌相关性的研究甚少,故本文将从CD47的分子结构、生理功能、表达情况及与胰腺癌的相关性进行综述,并对胰腺癌的免疫治疗进行总结和展望。     

EGFR inhibition in EGFR-mutant lung cancer cells perturbs innate immune signaling pathways in the tumor microenvironment

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR-mutant non–small-cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR-mutant cells. Using EGFR-mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR-TKI treatment, we found that EGFR-mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first-generation EGFR-TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre-treatment samples. Monocyte-derived macrophages facilitated antibody-dependent cellular phagocytosis when EGFR-TKI-treated EGFR-mutant cells were incubated with anti-CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR-mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell-free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP-1 monocytes in a stimulator of interferon genes-dependent manner. Our study indicates that EGFR inhibition in EGFR-mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR-mutant NSCLC.     

靶向CD47的抗肿瘤抗体研究进展

CD47是个多能分子,在肿瘤细胞逃避免疫监视过程中扮演重要角色,阻断CD47信号通道能有效激发巨噬细胞对肿瘤细胞的吞噬作用,成为非常有前景的肿瘤免疫治疗新途径。靶向CD47的单克隆抗体已成为近年来研究的新热点,目前的实验进展顺利,有必要进行更详尽的研究,使其早日进入临床应用。     

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.     

CD95L mediates tumor counterattack in vitro but induces neutrophil-independent tumor rejection in vivo

Many tumors express CD95L (CD178, FasL, APO-1L) and may thus kill tumor-infiltrating lymphocytes, a phenomenon called tumor counterattack. However, presently it is not clear whether tumor counterattack is a relevant immune escape mechanism. To characterize the effect of CD95L expression of tumor cells on tumor-specific T cells, we established an in vitro system with TCR tg T cells and a model tumor antigen. Preactivated antitumor T cells were able to kill CD95L(-) and CD95L(+) tumor cells. CD95L(+) tumor cells killed activated T cells in vitro and inhibited the expansion of cytotoxic antitumor T cells in mixed lymphocyte tumor reactions. In vivo CD95L expression led to delayed tumor growth or complete tumor rejection. Neutrophils were not responsible for the delayed growth of the CD95L(+) tumors tested. In mice with neutrophils deficient for important cytotoxicity mechanisms (p47phox(-/-) or iNOS(-/-) mice), CD95L(+) tumors grew similarly as in wild-type mice. Incidence and growth rate of CD95L(+) tumors in mice injected with a neutrophil-depleting or an isotype control antibody was the same. In CD95-deficient lpr mice, tumor growth was not altered as compared to wild-type mice. Taken together, CD95L mediated tumor counterattack in vitro, but led to neutrophil-independent tumor rejection in vivo.     

Diagnostic utility of programmed cell death ligand 1 (clone SP142) immunohistochemistry for malignant lymphoma and lymphoproliferative disorders: A brief review

The programmed cell death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in tumor cell escape from immune control and has been most extensively investigated for therapeutic purposes. However, PD-L1 immunohistochemistry is still not used widely for diagnosis. We review the diagnostic utility of PD-L1 (by clone SP142) immunohistochemistry in large-cell lymphomas, mainly consisting of classic Hodgkin lymphoma (CHL) and diffuse large B-cell lymphoma (DLBCL). Neoplastic PD-L1 (nPD-L1) expression on Hodgkin and Reed-Sternberg cells is well-established among prototypic CHL. Of note, EBV+ CHL often poses a challenge for differential diagnosis from peripheral T-cell lymphoma with EBV+ non-malignant large B-cells; their distinction is based on the lack of PD-L1 expression on large B-cells in the latter. The nPD-L1 expression further provides a good diagnostic consensus for CHL with primary extranodal disease conceivably characterized by a combined pathogenesis of immune escape of tumor cells and immunodeficiency. Compared with CHL, the nPD-L1 expression rate is much lower in DLBCL, highlighting some specific subgroups of intravascular large B-cell lymphoma, primary mediastinal large B-cell lymphoma, and EBV+ DLBCL. They consist of nPD-L1-positive and -negative subgroups, but their clinicopathological significance remains to be elucidated. Microenvironmental PD-L1 positivity on immune cells may be associated with a favorable prognosis in extranodal DLBCL. PD-L1 (by SP142) immunohistochemistry has helped us to understand the immune biology of lymphoid neoplasms possibly related by immune escape and/or immunodeficiency. However, knowledge of these issues remains limited and should be clarified for diagnostic consensus in the future.