免疫检查点B7-H3在肝胆胰恶性肿瘤中的研究进展

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免疫检查点B7-H3在肝胆胰恶性肿瘤中的研究进展

来源：中华普通外科杂志作者：中华普通外科杂志时间：2023-05-22 阅读：5551评论：0赞：0 有0人参与

免疫检查点B7-H3在肝胆胰恶性肿瘤中的研究进展

张杰凌晓锋修典荣

北京大学第三医院普通外科

引用本文: 张杰, 凌晓锋, 修典荣. 免疫检查点B7-H3在肝胆胰恶性肿瘤中的研究进展 [J] . 中华普通外科杂志, 2023, 38(4) : 316-320. DOI: 10.3760/cma.j.cn113855-20220626-00414.

消化系统肿瘤包括食管癌、胃癌、结直肠癌、胰腺癌、肝癌等^［1］，占全球癌症相关发病率和死亡率50%以上^［2］。其中又以胆胰恶性肿瘤预后最差，总体的5年生存率不足10%^［3］，肝癌为18%^［4］。其共同的特点是早期诊断困难，多数诊断即晚期，失去手术机会。

近年来，免疫治疗在肿瘤治疗领域取得了较显著的成果。B7超家族是一类表达在抗原呈递细胞表面的跨膜蛋白，在T细胞免疫共抑制过程中发挥重要的作用^［5］。B7超家族成员包括：白细胞分化抗原80（CD80，B7.1）、CD86（B7.2）、B7-H1［程序性死亡受体-配体1（PD-L1）或CD274］、B7-DC（PD-L2或CD273）、B7-H2、B7-H3（CD276）、B7-H4、B7-H5、B7-H6、B7-H7等。多项研究表明B7超家族成员在实体瘤细胞上的异常表达可能介导肿瘤免疫逃逸，从而促进肿瘤的增殖和侵袭^［6］。肿瘤的免疫治疗是当前研究的热点问题，本文聚焦B7-H3在肝胆胰恶性肿瘤中的研究进展进行综述。

一、

程序性死亡受体1（PD-1）与PD-L1

B7超家族包括众多成员，其中最具代表性的是B7-H1，即PD-L1。PD-1与PD-L1结合，可抑制T细胞的功能，导致免疫抑制；而阻断PD-1/PD-L1通路可恢复T细胞功能，解除肿瘤微环境中的免疫抑制状态，进而发挥抗肿瘤的作用^［7］。PD-1拮抗剂在美国、欧盟以及日本分别于2014年和2015年被批准用于治疗黑色素瘤和非小细胞肺癌。

对于晚期肝癌，免疫治疗正在快速兴起。纳武单抗（PD-1抗体）是美国食品药品监督管理局批准的第一个肝癌免疫检查点抑制剂^［8］。一项Ⅰ/Ⅱ期临床试验表明，PD-1抗体联合细胞毒性T淋巴细胞相关蛋白4（CTLA-4）抗体用于治疗肝细胞癌具有潜在的积极效果^［9］。

目前，多项Ⅰ期和Ⅱ期临床试验正在进行，旨在评估多药联合免疫治疗胆囊癌的疗效，包括纳武单抗（PD-1抗体）和伊匹单抗（CTLA-4抗体、NCT02834013、NCT02923934、NCT03101566）、德瓦鲁单抗（PD-L1抗体）和替西木单抗（CTLA-4抗体、NCT02821754）等组合。有研究表明PD-1抗体联合仑伐替尼用于治疗晚期胆囊癌疗效较好^［10］。Junho等前瞻性地纳入12例经一线化疗（吉西他滨+顺铂）后胆囊癌进展的患者，对其应用派姆单抗（PD-1抗体）作为二线治疗，客观有效率为16.7%。

2019年美国临床肿瘤学会报告了KEYNOTE-158研究（Ⅱ期临床研究）结果，该研究共纳入104例患者，应用派姆单抗（PD-1抗体）治疗晚期胆管癌，其中6例部分缓解，中位无进展生存时间为2个月，总体生存时间（OS）为9.1个月，显示出一定的抗肿瘤活性^［11］。不少应用PD-1/PD-L1抗体治疗胆管癌的临床试验仍在进行当中^［12］。

目前已有的临床试验结果显示，免疫检查点抑制剂单药治疗胰腺癌的疗效不甚理想^［13］。新近开展的临床研究大多是探究免疫检查点抑制剂（PD-1抗体、PD-L1抗体、CTLA-4抗体及其他^［14］）联合放化疗、靶向治疗等治疗胰腺癌的效果。

二、

B7-H3

B7-H3，亦称CD276，也是B7超家族其中一员，于2001年首次被发现^［15］，与其他B7家族成员的同源性达30%。

（一）B7-H3的结构与表达

B7-H3包括IgC和IgV样结构域以及高度多样的细胞质结构域^［15］。其位于人体第15号染色体上能够编码316个氨基酸，存在两种异构体：2Ig B7-H3和4Ig B7-H3，其中后者是主要存在形式^{［16, 17］}。

B7-H3的mRNA广泛表达于肝脏、胰腺、胃肠道、子宫、睾丸、前列腺等多种组织，但其蛋白水平在正常组织中表达量较低^{［15, 16, 17, 18］}。B7-H3转录后调控可能导致了其在转录水平和蛋白水平的表达差异，但具体的机制尚不明确^［19］。而其在多种恶性肿瘤组织（如肝癌、胰腺癌、胶质瘤、肺癌、结直肠癌、子宫内膜癌、骨肉瘤、卵巢癌、乳腺癌、肾癌、口腔鳞癌等）中则呈现高蛋白表达水平，且与恶性程度、预后等密切相关^{［20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32］}。

（二）B7-H3在肿瘤进展中的作用

早期研究中B7-H3被认为是一种共刺激因子，其能够促进CD4⁺及CD8⁺T细胞增殖和增强细胞毒效应^［33］。然而，越来越多的研究发现B7-H3在肿瘤免疫中扮演着共抑制作用，其与T细胞表面受体结合，抑制T细胞的生长和分化^［34］。此外，B7-H3也能抑制自然杀伤（NK）细胞的活性^［35］。再者，B7-H3可减少干扰素（IFN）-γ、肿瘤坏死因子（TNF）-α和其他细胞因子，如白介素（IL）-13，IL-10和IL-2的分泌^［36］。因此肿瘤细胞中异常表达的B7-H3可能参与介导肿瘤免疫逃逸^［37］。

体外细胞实验表明B7-H3可以促进肿瘤细胞侵袭和转移^［38］。其机制^［39］如下：①促进表达转移相关蛋白，例如基质金属肽酶2（MMP2）、信号转导和转录激活因子3（STAT3）、IL-8；②提高趋化因子受体4（CXCR4）表达水平，激活蛋白激酶B（AKT）、细胞外调节蛋白激酶（ERK）和Janus激酶2（JAK2）/STAT3通路；③激活JAK2/STAT3/MMP9通路；④激活Toll样受体（TLR）/核因子κB（NF-κB）通路，增加IL-8和血管内皮生长因子（VEGF）的表达。

此外，研究表明B7-H3表达与肿瘤组织中新生血管生成有关。在结肠癌中，其通过NF-κB途径上调VEGF受体的表达来促进肿瘤血管生成^［40］。

再者，B7-H3的异常表达导致肿瘤细胞耐药，降低化疗敏感性^{［41, 42］}。在结直肠癌中，Shi等^［43］发现B7-H3通过促进己糖激酶2（HK2）的表达来增加肿瘤细胞的葡萄糖消耗和乳酸生成，而HK2是B7-H3诱导的结直肠癌化疗耐药的关键介质。

B7-H3的生物特性及其和PD-L1之间的相似性使得研究人员有理由将其作为新的免疫治疗靶点投入研究。

（三）B7-H3免疫抑制剂

靶向B7-H3分子的肿瘤免疫抑制剂正在快速发展。在动物肿瘤模型当中，其单克隆抗体可提高肿瘤微环境中CD8⁺T细胞和NK细胞的浸润密度和延长生存时间^［44］。Enoblituzumab（MGA271）和Omburtamab（8H9），是两个人源化的抗B7-H3单克隆抗体，其被证实在泌尿及神经系统肿瘤治疗中具有一定的成效^{［45, 46, 47］}。此外，以B7-H3为靶点的抗体耦联药物和嵌合抗原受体T细胞免疫疗法（CAR-T）在多种实体瘤中显示了良好的抗肿瘤活性^{［48, 49, 50］}。

三、

B7-H3与肝胆胰恶性肿瘤

目前，关于B7-H3在肝胆胰恶性肿瘤方面的研究不多，尚无成熟上市的B7-H3抗体临床应用于该领域。

（一）B7-H3与肝癌

肝癌为全球第六大癌症，也是排名第三的癌症死因^［2］，其中75%的肝癌发生在亚洲^［51］。肝细胞癌占所有原发性肝癌的75%~85%^［2］，病毒性肝炎（乙肝、丙肝为主）是肝癌的主要病因^［52］。肝癌的预后差，总体5年生存率仅为18%（局部肿瘤为31%，区域扩散为11%，远处转移为3%）^［53］。

Sun等^［24］对240例术后肝细胞癌标本进行B7-H3免疫组化染色，其中93.8%标本中B7-H3表达异常，32.9%为强表达，37.1%为中等强度表达。相反，94.2%的癌旁组织低表达B7-H3。强/中等程度表达B7-H3是复发的独立危险因素（HR=1.79，P=0.005），且患者生存率明显降低（P=0.009）。B7-H3高表达与肿瘤侵袭、血管浸润及转移潜能相关，造成了肝细胞癌的不良预后。Kang等^［54］发现B7-H3介导的STAT3信号通路是诱导肿瘤相关巨噬细胞M2型极化，从而加速肝细胞癌的疾病进展的重要机制。他们应用体外细胞实验验证了B7-H3能够通过JAK2/STAT3/Slug信号通路靶向上皮-间充质转化（EMT）刺激肝癌的侵袭与转移^［55］。

（二）B7-H3与胆囊癌

胆囊癌是起源于胆囊黏膜上皮的恶性肿瘤，也是胆道系统最常见（80%~95%）的恶性肿瘤^［56］。大多数胆囊癌患者长期无症状，诊断时即处于疾病晚期^［57］，其预后差，总体的5年生存率仅为5%^［56］（0期为80%，Ⅰ期为50%，Ⅱ期为28%，Ⅲa期为8%，Ⅲb期为7%，Ⅳa期为4%，Ⅳb期为2%^［58］）。

Liu等^［59］检测了126例胆囊癌术后组织标本，B7-H3的阳性表达率为66.67%。其中，病理低分化者B7-H3阳性表达率显著高于中-高分化者（90.9% 比58.1%，P=0.004 7），癌肿高浸润程度者有更高的B7-H3的阳性表达率（T2~T4：60.6%，T1：33.3%，P=0.004 1），且胆囊癌复发患者B7-H3阳性表达率高于初发患者（93.3%比55.6%，P=0.015）。因此，可以推测，B7-H3的高表达可能有助于胆囊癌的早期诊断及术后生存及复发的评估。

（三）B7-H3与胆管癌

胆管癌是一种起源于胆管上皮细胞且具有较高恶性程度的肿瘤，约占消化道恶性肿瘤的3%^［60］。在过去40年，其发病率持续增加^［61］。根据解剖位置可分为肝内胆管癌（约20%）、肝门胆管癌（Klatskin瘤，50%~60%）和远端胆管癌（20%~30%），后两者合称肝外胆管癌。多数胆管癌患者就诊时即晚期，其预后很差，总体5年生存率约为10%^［3］。其中，早期胆管癌的5年生存率为30%，区域淋巴结转移者为24%，远处转移者仅为2%^［62］。

有学者发现B7-H3在57.8%的肝内胆管癌标本中阳性表达，其与淋巴结转移（P=0.007）和血管侵犯（P=0.017）显著相关。多因素分析显示B7-H3阳性表达是肝内胆管癌患者更短的OS和肿瘤特异性生存时间的独立预测因素^［63］，这表明免疫检查点B7-H3对于肝内胆管癌的治疗具有一定的潜在价值。尚无肝外胆管癌中B7-H3表达情况的相关研究报道。

（四）B7-H3与胰腺癌

胰腺癌的发病率在世界范围内呈现持续上升趋势^［64］。其中约95%起源于胰腺导管细胞，作为预后极差的消化道肿瘤，其总体5年生存率约6%^［65］。胰腺癌早期诊断困难，仅约20%的患者在诊断时为可切除病变^{［66, 67］}。据统计，ⅠA、ⅠB、ⅡA、ⅡB以及Ⅲ期（美国癌症联合委员会第8版分期系统）患者的中位OS分别为73.5、41.9、24.2、18.3和16.8个月^［68］。

有研究^［30］表明66%（99/150）的胰腺癌组织标本中阳性表达B7-H3蛋白，且高表达B7-H3与更短的术后无病生存期显著相关（HR=3.12，P=0.002 6）。这种关联程度在病理Ⅰ~Ⅱ期（HR=3.10，P<0.000 1）中比病理Ⅲ~Ⅳ期（HR=1.2，P=0.55）中更加明显。因此，B7-H3的表达可能是鉴别早期胰腺癌的潜在预后生物标志物。在体外细胞实验中，通过干扰RNA敲低B7-H3可减慢高达50%的细胞迁移及Transwell侵袭。在皮下移植瘤小鼠模型中，敲低B7-H3基因减缓了肿瘤生长速度。在原位移植胰腺癌小鼠模型中，通过敲低B7-H3可以减少胰腺癌的体内转移^［69］。Xie等^［70］证明可溶性B7-H3上调TLR4的表达，接着激活NF-κB通路，最终促进IL-8以及VEGF表达，参与胰腺癌细胞的侵袭和转移。

四、

总结与展望

肝胆胰恶性肿瘤具有高侵袭性、易转移、早期复发等特点，特别是胆胰系统恶性肿瘤早期诊断困难，多数发现即晚期，预后极差。近年来，肿瘤的免疫治疗成为学术界的研究热点，其中研究最广泛的免疫检查点PD-1/PD-L1和CTLA-4，均在肝胆胰恶性肿瘤领域中进入临床试验阶段。而同属B7家族的免疫检查点B7-H3在该领域处于初步探索阶段，其高表达提示肿瘤有更强的侵袭及转移特性，对预后不良有一定的指示意义。其作为免疫治疗靶点对肿瘤的辅助及挽救治疗存在潜在价值，对其信号通路的进一步研究，有助于研究者深入了解B7-H3在免疫细胞和肿瘤细胞之间的调控机制，不断挖掘并扩展其临床应用价值。

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