协同刺激分子B7-H4与恶性肿瘤关系的研究进展

B7-H4是最新发现的B7家族新成员,广泛分布在非淋巴组织中,表达于多种免疫细胞表面,通过抑制免疫细胞的抗肿瘤功能从而促进肿瘤免疫逃逸。B7-H4在实体瘤中有异常高表达,在细胞的恶性转化和肿瘤的发生、发展及转移中具有重要意义,对B7-H4的研究有助于寻找新的恶性肿瘤的早期诊断指标、治疗及判断预后的分子靶点。本文就B7-H4的结构、分布、生物学作用及其与恶性肿瘤生物学行为的关系作一概述。     

协同刺激分子B7-H4在消化系统肿瘤中的研究进展

协同刺激分子B7-H4是B7家族的一个新成员,它通过抑制T细胞的增殖活化、阻碍细胞因子的合成和细胞周期的进程来下调免疫应答.B7-H4广泛分布在非淋巴组织中,高表达于多种恶性肿瘤并参与肿瘤的发生发展及预后.B7-H4在消化道系统肿瘤中的高表达可能使其成为新的肿瘤标志物及早期诊断指标,为免疫治疗提供新的依据.全文就消化道系统肿瘤中B7-H4的研究进展进行综述.     

B7-H3在恶性肿瘤中的研究进展

B7-H3（CD276）是B7和CD28家族重要的免疫检查点成员,在多种恶性肿瘤中均有表达,并且与恶性肿瘤的生长、转移、复发、预后不良等因素密切相关,与此同时还通过T细胞参与恶性肿瘤的免疫过程。近年来随着研究的深入,人们发现B7-H3在恶性肿瘤中不但是一种共刺激分子,而且对调节性T细胞（regulatory cells,Treg）具有共抑制作用。虽然目前尚未确定它的受体部分,但其分子靶点被认为是一种具有前景的免疫治疗研究方向。本文就B7-H3在恶性肿瘤中的研究进展作一综述。     

共刺激分子B7-H4在妇科恶性肿瘤中的研究进展

肿瘤的发生不仅与外界多种致癌因素有关,还与机体自身免疫应答及遗传因素密切相关。B7-H4为新近发现的免疫共刺激调节蛋白B7家族新成员,多种恶性肿瘤过表达。B7-H4作为免疫反应的第二信号,调节免疫活性,参与肿瘤的发生、发展和预后。本文针对免疫共刺激分子B7-H4 的结构、功能及其与妇科恶性肿瘤的关系作一综述。     

负性共刺激分子B7-H1和B7-H4在结直肠癌中的表达及其临床意义

目的:检测结直肠癌组织中负性共刺激分子B7-H1和B7-H4的表达、T细胞亚群的浸润情况,探讨其临床意义。方法:收集苏州大学附属第四医院2003年1月至2003年12月50例结直肠癌患者的癌组织标本以及5例患者的癌旁组织标本,免疫组织化学法检测结直肠癌组织中B7-H1和B7-H4的表达以及T细胞亚群的浸润,分析B7-H1、B7-H4的表达与结直肠癌患者临床病理特征及T细胞浸润的相关性,分析B7-H1、B7-H4的表达和CD3+T、CD8+T淋巴细胞浸润程度与患者预后的相关性。结果:结直肠癌组织高表达B7-H1(44%)和B7-H4(56%),而癌旁组织不表达(P<0.01)。B7-H1在结肠癌组织中的表达较直肠癌显著升高(P<0.05);随着Duke’s分期的升高,B7-H4的表达水平也呈上升趋势(P<0.05)。结直肠癌组织中B7-H1的表达与CD3+T细胞浸润呈负相关(P<0.05),但与B7-H4的表达无关。B7-H1的表达水平与患者预后呈负相关(P<0.05),且B7-H1和B7-H4同时高表达的患者总体生存率显著降低(P<0.05)。结论:负性共刺激分子B7-H1和B7-H4在人结直肠癌组织中高表达,并与患者总体生存率相关,两者的共同检测对结直肠癌诊断和预后判断具有一定的临床价值。     

肿瘤组织中B7-H4的表达及意义

B7-H4是共刺激分子B7家族的新成员,B7-H4通过抑制T细胞的增殖、细胞因子的产生和细胞周期的进行对T细胞免疫进行负调控.近期研究表明,B7-H4与肿瘤的发生发展有着密切关系,是肿瘤诊断和治疗的重要指标.     

妇科肿瘤免疫治疗的新靶点

虽然作用于程序性细胞死亡蛋白1/程序性死亡配体 1（PD-1/PD-L）和细胞毒性 T淋巴细胞抗原4（CT- LA4）的抗体已成功应用于晚期实体瘤的治疗,但其疗效仍不够高。需寻找新的免疫靶点以便为难治性肿瘤患者寻求替代治疗。根据受体与配体结合后发挥的作用,可将免疫靶点分为共刺激分子和共抑制分子,共抑制分子包括∶T细胞免疫球蛋白黏蛋白-3（TM-3）、含免疫球蛋白及 ITM 结构域的T 细胞免疫受体（TGIT）、淋巴细胞活化基因3（LAG-3）、T细胞激活抑制物免疫球蛋白可变区结构域（VISTA）以及 B7家族的 B7-H3 和 B7-H4;共刺激分子包括 CD27、OX40、4-1BB、CD40,糖皮质激素诱导的肿瘤坏死因子受体（GITR）和诱导共刺激因子（ICOS）等。本文就新兴的免疫靶点在妇科恶性肿瘤的临床前和临床研究进展作一简要阐述。     

B7-H1及其受体与肿瘤免疫逃逸

B7-H1是近年来发现的B7家族的一个新成员。B7-H1与相应受体结合后，对T细胞、B细胞的功能有重要影响。近期研究发现许多肿瘤的细胞表面亦可大量表达B7-H1和相应受体：肿瘤细胞表达的B7-H1与其受体结合能抑制机体的特异性细胞免疫和体液免疫，参与肿瘤的免疫逃逸。阻断B7-H1与其受体的结合将是肿瘤治疗的一条新途径。现综述近年来B7-H1与肿瘤免疫逃逸的研究进展。     

B7-H1及其受体与肿瘤免疫逃逸

B7-H1是近年来发现的B7家族的一个新成员.B7-H1与相应受体结合后,对T细胞、B细胞的功能有重要影响.近期研究发现许多肿瘤的细胞表面亦可大量表达B7-H1和相应受体.肿瘤细胞表达的B7-H1与其受体结合能抑制机体的特异性细胞免疫和体液免疫,参与肿瘤的免疫逃逸.阻断B7-H1与其受体的结合将是肿瘤治疗的一条新途径.现综述近年来B7-H1与肿瘤免疫逃逸的研究进展.     

妇科肿瘤免疫治疗的新靶点

虽然作用于程序性细胞死亡蛋白1/程序性死亡配体 1（PD-1/PD-L）和细胞毒性 T淋巴细胞抗原4（CT- LA4）的抗体已成功应用于晚期实体瘤的治疗，但其疗效仍不够高。需寻找新的免疫靶点以便为难治性肿瘤患者寻求替代治疗。根据受体与配体结合后发挥的作用，可将免疫靶点分为共刺激分子和共抑制分子，共抑制分子包括∶T细胞免疫球蛋白黏蛋白-3（TM-3）、含免疫球蛋白及 ITM 结构域的T 细胞免疫受体（TGIT）、淋巴细胞活化基因3（LAG-3）、T细胞激活抑制物免疫球蛋白可变区结构域（VISTA）以及 B7家族的 B7-H3 和 B7-H4;共刺激分子包括 CD27、OX40、4-1BB、CD40，糖皮质激素诱导的肿瘤坏死因子受体（GITR）和诱导共刺激因子（ICOS）等。本文就新兴的免疫靶点在妇科恶性肿瘤的临床前和临床研究进展作一简要阐述。     

协同刺激分子PD-L1、B7-H3与B7-H4在卵巢癌中的表达及其意义

协同刺激分子PD-L1、B7-H3与B7-H4可与T细胞及其受体结合并抑制T细胞的增殖和过度活化,在细胞免疫应答过程中起重要的调控作用,已被多项研究证明与肿瘤的免疫原性及肿瘤的发生、发展密切相关。这3种分子在正常卵巢组织中均不表达,而在卵巢癌组织中呈不同程度的高表达,它们可能在促进卵巢癌的发生、转变及病情进展过程中起重要作用,研究其作用机制对卵巢癌的早期诊断及靶向治疗有一定的意义。     

Effect of TLR4 and B7-H1 on Immune Escape of Urothelial Bladder Cancer and its Clinical Significance

Background/Aim: Toll-like receptor 4 (TLR4) and B7-H1, both normally expressed restricted to immune cells,are found to be aberrantly expressed in a majority of human tumors and may play important roles in regulationof tumor immunity. It has been shown that urothelial bladder cancer (UBC) patients can manifest tumoralimmune escape which may be a potential critical factor in tumor pathogenesis and progression. However, so far,the mechanisms of UBC-related immune escape have not been clarified. The aim of this study was to investigatethe effect of TLR4 and B7-H1 on immune escape of UBC. Methods: Bladder cancer T24 cells were pre-incubatedwith LPS and co-cultured with tumor specific CTLs. CTL cytotoxicity and apoptosis rates were measured by MTTassay and flow cytometry, respectively. The effects of an ERK inhibitor on B7-H1 expression and CTL cytotoxicityagainst T24 cells were also evaluated. In addition, TLR4, B7-H1 and PD-1 protein expression was analyzed byimmunohistochemistry in 60 UBC specimens and 10 normal urothelia. Results: TLR4 activation protected T24cells from CTL killing via B7-H1 overexpression. However PD98059, an inhibitor of ERK, enhanced CTL killingof T24 cells by reducing B7-H1 expression. TLR4 expression was generally decreased in UBC specimens, whileB7-H1 and PD-1 were greatly overexpressed. Moreover, expression of both B7-H1 and PD-1 was significantlyassociated with UICC stage and WHO grade classification. Conclusions: TLR4 and B7-H1 may contribute toimmune escape of UBC. Targeting B7-H1 or the ERK pathway may offer new immunotherapy strategies forbladder cancer.     

Clinical significance and regulation of the costimulatory molecule B7-H1 in pancreatic cancer

We investigated the expression pattern and clinical significance of the costimulatory ligands B7-1, B7-2, B7-H1, and B7-DC, and their counter-receptors CTLA-4 and PD-1 in pancreatic cancer. Gene expression of all examined costimulatory molecules was significantly upregulated in pancreatic cancer tissues. B7-1, B7-2, B7-H1, and B7-DC protein was detectable in pancreatic cancer cells. Only the expression of B7-H1 significantly correlated with postoperative survival (p<0.0001). B7-H1 was inducible in cultured pancreatic cancer cells by IFN-gamma and significantly correlated with the level of IFN-gamma expression in human pancreatic cancer tissues (Spearman rho=0.4536,p=0.0029). B7-H1 positive tumors showed an increased prevalence of tumor-infiltrating regulatory T cells (T(regs)) compared to B7-H1 negative tumors. Among the investigated costimulatory molecules only tumor-associated B7-H1 seems to be of prognostic relevance in pancreatic cancer. B7-H1 might, therefore, be involved in the downregulation of antitumor responses through regulation of T(regs) in pancreatic cancer. Our findings also suggest a dual role of IFN-gamma in antitumor response. Through induction of B7-H1 in pancreatic cancer cells IFN-gamma might contribute to the evasion of antitumor immunity.     

T-cell infiltration and expressions of T lymphocyte co-inhibitory B7-H1 and B7-H4 molecules among colorectal cancer patients in northeast China’s Heilongjiang province

Colorectal cancer has an extremely poor prognosis due to its high rate of recurrence and metastasis. The present study aimed to investigate the correlations between the B7-H1 and B7-H4 expressions as well as the clinicopathological characteristics and the prognosis of patients with colorectal cancer. We further inferred from these findings whether T lymphocyte co-inhibitory molecules (B7-H1 and B7-H4) led to a poor prognosis in Heilongjiang patients with colorectal cancer. Survival analysis revealed that the poor prognosis of these patients was unrelated to patient age, tumor size or histological grade, or lymph node metastasis, but was associated with TNM stage, high B7-H1 and B7-H4 expression levels. High B7-H1 and B7-H4 expressions were closely correlated with poor prognosis in patients with colorectal cancer. We speculate that the joint detection of these molecules may clinically apply for diagnosing and predicting poor prognosis of patients with colorectal cancer in northeast China’s Heilongjiang province. In addition, intervention of B7-H1 and B7-H4 may be beneficial for enhancement of immunity in these patients.     

OPN和B7-H4在上皮性卵巢肿瘤中的表达及意义

背景与目的:上皮性卵巢癌的发生涉及多方面的因素。近年的研究表明骨桥蛋白(osteopontin,OPN)与多种肿瘤的发生发展有关,但其在卵巢癌中的研究较少;而B7-H4是新近发现的肿瘤标志物,其在卵巢癌中的研究也很少。本研究旨在探讨卵巢上皮性肿瘤中OPN和B7-H4的表达及其临床意义。方法:采用免疫组化法检测15例正常卵巢组织、20例卵巢良性肿瘤组织、20例卵巢交界性肿瘤组织、40例卵巢癌组织标本中OPN和B7-H4的表达情况,分析两者表达与卵巢癌临床病理特征的关系。结果:OPN和B7-H4在上皮性卵巢癌组织中的表达高于卵巢交界性及良性、正常卵巢组织,各组之间的差异有统计学意义(P<0.05)。OPN和B7-H4在低分化卵巢癌中的阳性率均显著高于高、中分化卵巢癌(P<0.05),Ⅲ～Ⅳ期卵巢癌中的阳性率亦显著高于Ⅰ～Ⅱ期卵巢癌(P<0.05)。OPN阳性者伴有较高的淋巴结转移率(P<0.05),而与年龄、组织学类型无关;B7-H4在卵巢浆液性癌中的阳性率显著高于黏液性癌(P<0.05),而与年龄、淋巴结转移等无关。结论:OPN、B7-H4在上皮性卵巢癌中表达升高,可为卵巢恶性肿瘤的诊断提供参考。     

Targeted silencing of TRPM7 ion channel induces replicative senescence and produces enhanced cytotoxicity with gemcitabine in pancreatic adenocarcinoma

B7-homolog 4 (B7-H4), a recently identified homolog of B7.1/2 (CD80/86), has been described to exert co-stimulatory and immune regulatory functions. We investigated the expression and the functional activity of B7-H4 in lung cancer in vitro and in vivo. Although a lung cancer cell line constitutively expressed B7-H4 mRNA and protein in plasma, primary tumor cell isolated from the transplanted lung carcinoma model expressed B7-H4 on the surface. Interestingly, in transplanted lung carcinoma model, the expression of membrane-bound B7-H4 in tumor cells was increased as prolonging of tumor transformation. Exposure to tumor-associated macrophages strongly induced membrane-bound B7-H4 expression on the lung cancer cell line. To elucidate the functional significance of lung cancer-related B7-H4 expression, we performed co-culture experiments of lung cancer cell with allo-reactive T cells. Lung cancer-related B7-H4 was identified as a strong inhibitor of T-cell effect. Furthermore, B7-H4 mAb had an ability to inhibit tumor growth in vivo. B7-H4 expression may thus significantly influence the outcome of T-cell tumor cell interactions and TAM induced membrane-bound B7-H4 on the lung cancer cell represents a novel mechanism by which lung cancer cells evade immune recognition and destruction.     

皮肤恶性肿瘤组织中B7-H1的表达及临床意义

目的 研究共刺激分子B7-H1在常见皮肤恶性肿瘤组织中的表达及其临床意义。方法 采用ElivsionTMplus免疫组织化学法检测B7-H1在51例鳞状细胞癌（SCC组）和93例非鳞状细胞癌共144例皮肤恶性肿瘤组织中的表达情况,同时选取10例日光性角化病（癌前病变组）和10例皮肤良性肿瘤（良性肿瘤组）作对照,分析B7-H1在癌前病变组、良性肿瘤组、SCC组及非鳞状细胞癌中的阳性表达率以及SCC中B7-H1表达水平与临床病理参数（年龄、性别、肿瘤大小、肿瘤部位、曝光部位及分化程度）间的关系。结果 B7-H1主要表达于皮肤肿瘤细胞的胞质及胞膜,呈弥漫性棕黄色颗粒状染色。B7-H1在癌前病变组、良性肿瘤组及SCC组的阳性表达率分别为10.0％（1／10）、40.0％（4／10）和76.5％（39／51）;在SCC中,B7-H1表达水平在不同年龄、性别、肿瘤大小、肿瘤部位、曝光部位及分化程度间的差异均无统计学意义（P＞0.05）。B7-H1在常见上皮来源的非鳞状细胞癌中均有表达,其中基底细胞癌、汗腺癌、乳房外Paget病、腺样囊性癌、皮脂腺癌及恶性黑色素瘤的阳性表达率依次为81.4％（35／43）、70.0％（7／10）、100.0％（3／3）、100.0％（2／2）、100.0％（1／1）和76.2％（16／21）。而在非上皮来源的隆突性纤维肉瘤中未见表达。结论 皮肤SCC组织中B7-H1表达率高于癌前病变和皮肤良性肿瘤组织,提示B7-H1可能参与了皮肤恶性肿瘤的发生与发展。     

B7-H4 gene polymorphisms are associated with sporadic breast cancer in a Chinese Han population

Background  

B7-H4, a co-inhibitory molecule of the B7 family, can restrain T cell proliferation, cytokine secretion and the development of cytotoxicity. B7-H4 is expressed in tumor tissues at a higher level than in normal tissues, and has a potential effect to protect tumors from anti-tumor immune responses. This case-control study was carried out to determine the potential influences of B7-H4 gene polymorphisms on the susceptibility and progression of breast cancer in Han women of Northeast China.