2020, Vol. 15
恶性肿瘤被称为癌症，表现为组织分化程度低，具有侵袭转移潜力。2018年全世界新发的癌症病例约1 810万，死亡约960万，其中，48.4%的新发病例和57.3%的死亡病例发生在亚洲[1]。在早期针对肿瘤的研究中，科学家发现动物肠道病毒对肿瘤具有一定杀伤作用，从而使溶瘤病毒的研究受到了关注。由于通常仅引起成人无症状或轻微病变[2-3]及突出的机体抗肿瘤免疫[4]，以肠道病毒为基础的溶瘤病毒受到广泛关注。本文针对肠道病毒的溶瘤作用研究进展进行综述。
1 肠道病毒概况肠道病毒(enterovirus，EV)是一类无包膜的单股正链RNA病毒，包括柯萨奇病毒(Coxsackievirus，CV)、脊髓灰质炎病毒(poliovirus，PV)、埃可病毒(Echovirus)以及新型肠道病毒71型(EV71)等。由于部分肠道病毒具有选择性杀死肿瘤细胞的能力，对正常细胞影响小，所以被作为溶瘤病毒[3, 5]。但是，也有研究证据支持肠道病毒能促进肿瘤发生、发展。EV71可引起辅助性T细胞17(T helper cell 17，Th17细胞)在结肠癌组织中募集并刺激细胞因子白细胞介素17(interleukin-17，IL-17)的产生，Th17细胞和IL-17两者在结肠癌的发生、发展以及转移和预后中均发挥了重要作用[6-10]。因此，肠道病毒在肿瘤的发生、发展中发挥何种作用，仍需更多的证据支持。
2 肠道病毒的溶瘤作用 2.1 肠道病毒作为溶瘤病毒的证据 2.1.1 经典证据1971年，动物肠道病毒的溶瘤现象首次被观察到。研究发现，牛肠病毒可使小鼠Ehrlich癌性腹水减少、肉瘤团块缩小，白血病小鼠寿命延长[11]。牛肠病毒能在多种肿瘤细胞中良好复制，产生致细胞病变效应[12]，使移植入家兔体内的人类肿瘤明显减小[13]。柯萨奇病毒B(Coxsackievirus B，CVB)、猪肠病毒能在肿瘤细胞中增殖并杀伤肿瘤细胞[14]，埃可病毒也可在多种结肠癌细胞系中有效复制并杀伤肿瘤细胞[15]。
2.1.2 肠道病毒受体在肿瘤细胞表面过表达肠道病毒受体在正常组织中低表达，在多种肿瘤组织中过表达。脊髓灰质炎病毒受体CD155在神经系统肿瘤、骨和软组织肉瘤等多种人类肿瘤细胞表面过表达[16-17]。将脊髓灰质炎病毒减毒活疫苗作为溶瘤制剂应用时，可抑制移植上述肿瘤的实验动物模型体内肿瘤生长[18-19]，明显提高肿瘤发生脑转移实验动物的生存率，再次接种相同种类的癌细胞，也不会再引发癌症[18]。作为柯萨奇病毒A21(Coxsackievirus A21，CVA21)的受体，细胞间黏附分子1(intercellular adhesion molecule-1，ICAM-1)和衰变加速因子(decay-accelerating factor，DAF)在乳腺癌、前列腺癌、黑素瘤等细胞膜表面表达量丰富。给予小鼠CVA21后，小鼠的原位肿瘤表现出溶瘤现象，远处肿瘤和转移灶也被消除[20-21]，这表明溶瘤效应有量效反应作用[20]。埃可病毒主要与细胞表面的整合素α 2 β 1的α亚单位Ⅰ区结合，能够选择性地破坏表达高水平整合素的前列腺癌、卵巢癌和胃癌的细胞团，显著抑制腹水形成[22]。由于肠道病毒对受体的选择性，特定的肠道病毒能靶向抑制特定组织来源的肿瘤[3]。
2.1.3 宿主免疫对肠道病毒的溶瘤作用无影响有研究报道，当肠道病毒感染时，机体对肠道病毒的清除作用不影响肠道病毒的溶瘤作用。接种脊髓灰质炎病毒疫苗后机体产生的抗体，不会削弱肠道病毒的溶瘤效果[23]。给予黑色素瘤四期患者CVA13、15、18和21后，针对CVA21的抗体并不能交叉中和其他病毒亚型感染[24]。
2.2 肠道病毒溶瘤的作用机制 2.2.1 肠道病毒致细胞病变效应肠道病毒感染宿主细胞后，阻断了细胞蛋白质的生物合成过程，大量复制子代病毒，导致宿主细胞裂解，并在细胞间传播[25]。
2.2.2 肠道病毒激发宿主抗肿瘤免疫肠道病毒感染并裂解靶细胞后，释放的肿瘤抗原被邻近细胞捕获，通过外源性人类白细胞抗原(human leukocyte antigen，HLA)Ⅱ类呈递途径[26]，主要由CD8+ T细胞介导，促进免疫细胞识别肿瘤抗原，刺激机体抗肿瘤免疫[27-28]。给予神经母细胞瘤小鼠脊髓灰质炎病毒，肿瘤裂解后收集到的脾细胞溶瘤强度增强，主要由CD8+ T细胞介导[28]。而埃可病毒也可以通过该机制发挥抗肿瘤作用[29]。另一方面，在肿瘤所致的免疫抑制微环境中肠道病毒还能重新激活机体抗肿瘤免疫[30-31]，如重组溶瘤脊髓灰质炎病毒-鼻病毒嵌合体(recombinant nonpathogenic polio-rhinovirus chimera，PVS-RIPO)能激活被抑制的树突细胞(dendritic cell，DC)和巨噬细胞，DC分泌Ⅰ型干扰素(interferon，IFN)，产生强烈且持久的Ⅰ型IFN反应[32-34]。PVS-RIPO还可直接裂解肿瘤细胞[35]，促进以中性粒细胞浸润为主的天然免疫，为与获得性免疫产生协同作用提供了促炎微环境[36-37]。
2.2.3 肠道病毒能够诱导细胞凋亡细胞凋亡信号通路包括细胞表面的受体介导的和线粒体介导的细胞凋亡信号通路。脊髓灰质炎病毒感染可同时激活上述两条通路而诱导肿瘤细胞凋亡[19, 36]。EV71感染细胞后可激活线粒体介导内在的caspase-9凋亡通路[37]和Bax诱导的细胞凋亡[38-39]。EV71的3C蛋白也能通过裂解端粒结合蛋白PinX1促进细胞凋亡[40]。
3 肠道病毒溶瘤效果的优化策略 3.1 以提高溶瘤病毒的组织亲嗜性提升安全性安全性是溶瘤病毒的重要指标[41]。加强靶向性能提高溶瘤病毒的安全性，避免溶瘤制剂无效分布于正常组织，从而提高治疗指数。全身应用天然溶瘤病毒后，溶瘤病毒在肿瘤组织中的剂量常不足以达到免疫反应所需的临界阈值[31]。主要有两种途径提升组织亲嗜性，首先，通过基因工程向野生型溶瘤病毒插入器官特异性的miRNA靶序列，可改变溶瘤病毒在肿瘤细胞中的趋向性和生物分布[42]；其次，通过改变溶瘤病毒的传播及复制能力建立复制缺陷型病毒，以提高溶瘤的安全性和组织亲嗜性，如溶瘤病毒在特异感染肿瘤细胞的同时，对非肿瘤细胞也产生不同程度的影响。利用基因工程对溶瘤病毒进行改造，达到溶瘤病毒在发挥溶瘤作用的同时少干扰邻近正常细胞的效果。用外源基因如肿瘤抗原取代编码脊髓灰质炎病毒衣壳的基因，制造出的RNA复制子在衣壳包被后通过与脊髓灰质炎病毒相同的机制发挥溶瘤作用，但由于其不具有编码衣壳的基因，仅局限于单轮感染，对于低表达CD155的正常细胞杀伤作用不明显，且剂量可控，多次注射也能保证安全性[43]。另一项经典的研究是将脊髓灰质炎病毒的内部核糖体进入位点(internal ribosome entry site，IRES)，由人类2型鼻病毒(human rhinovirus type 2，HRV2)的基因替换，构建有复制缺陷的脊髓灰质炎/鼻病毒嵌合体(PVS-RIPO)。PVS-RIPO在正常细胞中复制能力减弱，但在肿瘤中作用不变，因此，被广泛用于溶瘤病毒的研究[44-45]。
3.2 通过变异增加溶瘤病毒的应用范围在肿瘤细胞表面常发生病毒特异受体下调或丢失[46]，导致溶瘤病毒的溶瘤效率低并产生副作用。促使病毒变异可改变受体的特异性，拓宽溶瘤病毒的应用范围。用肠道病毒受体缺陷的细胞连续传代病毒原型，得到的变异株有可能获得针对该细胞系增强的感染和复制效能，扩大溶瘤病毒的应用范围[47]。如将原型CVB3连续传代，致使病毒衣壳中VP3的一个谷氨酸位点被谷氨酰胺取代，CVB3由此获得结合DAF的能力，可感染柯萨奇病毒和腺病毒受体(Coxsackievirus and adenovirus receptor，CAR)缺陷但大量表达DAF的人横纹肌瘤(rhabdomyoma，RD)细胞[48]。CVB1、CVB3、CVB5和CVB6趋向性的拓宽可能与后天获得与DAF结合的能力有关[49]。CVA21进入细胞需同时与ICAM-1和DAF结合，而单独结合DAF的病毒不能感染细胞[50]。如果CVA21在仅表达DAF的细胞系中多次传代，得到的变异株CVA21-DAFv结合DAF的能力则更强，仅与DAF结合即可感染细胞。增加CVA21-DAFv的DAF受体利用率能使ICAM-1缺陷细胞快速且完全裂解，同时也保留了与ICAM-1结合的潜力[51]。
3.3 引入锤头型核酶提升病毒复制效率病毒复制时，去除脊髓灰质炎病毒RNA 5 ′端核苷酸的步骤降低了病毒的复制效率[52]。引入锤头型核酶能去除5 ′端多余的核苷酸，产生精确的5 ′端转录本，转录本的复制速度显著增加[53]。锤头型核酶克隆的设计可能会提高溶瘤病毒用于治疗的疗效。
3.4 溶瘤病毒作为导入抗原基因的载体溶瘤病毒可被改造成基因载体，携带抗原基因或肿瘤抗原基因。将CD8+ T细胞抗原基因引入小鼠脑脊髓炎病毒(Theiler’s murine encephalomyelitis virus，TMEV)基因组中，重组病毒可诱导实验动物产生大量抗肿瘤CD8+ T细胞，使体内肿瘤体积缩小和生存期延长[54]。有研究采用外源基因(如肿瘤抗原取代编码脊髓灰质炎病毒衣壳的基因)制备出重组溶瘤病毒。该重组溶瘤病毒对CD155低表达的正常细胞杀伤作用不明显。由于无法编码蛋白衣壳，该重组溶瘤病毒仅用于单轮感染，剂量容易控制，可以多次注射，安全性好[43]。
4 肠道病毒的临床应用 4.1 进入临床试验的肠道病毒肠道病毒适用于早期肿瘤的术后辅助治疗。PVS-RIPO已应用于恶性胶质瘤的临床试验，能提高患者的生存率，但也存在副作用[55]。埃可病毒能显著延长早期黑色素瘤术后患者的生存期，没有明显副作用[56]。CVA21、CVB3等溶瘤病毒是目前临床试验的重点[42]。
4.2 肠道病毒与抗癌药联合应用溶瘤病毒与传统化疗联合应用时呈现出协同作用，在一些耐化疗药物的结直肠肿瘤中，联合治疗具有显著的抗肿瘤作用[57-58]。当CVA21与盐酸多柔比星(阿霉素)同时使用或在盐酸多柔比星使用前24 h注射CVA21，中等程度表达CVA21受体的细胞死亡增加。与单独使用其中的一种相比，CVA21与盐酸多柔比星联合应用对于肿瘤的影响更显著[59]。奥沙利铂抑制肿瘤细胞DNA的复制和转录，但对奥沙利铂耐药的结肠癌患者预后较差[60]。CVA11在感染结肠癌细胞时，可有效裂解对奥沙利铂敏感的Caco-2细胞株，而对奥沙利铂耐药的WiDr株几乎没有影响。但用奥沙利铂预处理WiDr细胞系可使该细胞系在体内、外均被CVA11感染而裂解。联合CVA11与奥沙利铂治疗比单独使用其中之一更有效、更具细胞毒性[61]。派姆(Keytruda)单克隆抗体(简称单抗)是一种抗PD-1的抗体，能使肿瘤微环境中的T细胞数量增加，被用于恶性黑色素瘤等方面的治疗[62-63]。肿瘤微环境的免疫抑制可导致针对于派姆单抗的耐药性发生[64]。溶瘤病毒在一定程度上逆转了肿瘤免疫抑制并可诱导抗肿瘤T细胞反应。临床试验证实，将CVA21与派姆单抗联合用于晚期黑色素瘤，两者表现出协同作用，可有效提高抗肿瘤活性，且患者耐受性良好[65]。
4.3 肠道病毒溶瘤作用的安全性对于属小RNA病毒科的肠道病毒来说，病毒变异(如毒性减弱、亲嗜性改变等)需要关注。需通过基因工程技术改造病毒基因组，增加病毒复制的保真度，防止病毒毒力回复[61]。脊髓灰质炎病毒作为溶瘤病毒在胶质瘤中复制时没有出现上述病毒变异[66]。溶瘤病毒载体通过患者的排泄物可能影响环境问题，也需予以关注[67]。
5 需要解决的关键问题溶瘤病毒在肿瘤微环境中刚开始复制时对激活机体抗肿瘤免疫的影响，较病毒持续存在于肿瘤细胞内时更大[68]。在肿瘤微环境中，溶瘤病毒、肿瘤细胞、肿瘤微环境及宿主免疫四者之间复杂的相互作用关系仍需深入研究，为肠道病毒溶瘤机制的后续探索做铺垫[69]。
肠道病毒在人类与啮齿动物中的表现差异较大，其中，小鼠模型常缺乏免疫功能。例如，人类红细胞表面存在CAR受体，而小鼠和恒河猴模型的红细胞表面却没有，这些CAR受体能隔离柯萨奇病毒颗粒并将其快速清除[70]。该差异阻碍着溶瘤病毒研究从临床前阶段向临床阶段过渡[41]。另外，如何在保证安全性的基础上开发出更广谱、更具潜能的的溶瘤病毒，仍是未来需要解决的问题。
6 结语近年来，肠道病毒与肿瘤关系的研究受到关注，在肠道病毒溶瘤作用的分子机制以及肠道病毒改造与临床试验等方面已取得进展，但肠道病毒与肿瘤之间的关系、肠道病毒成为溶瘤病毒的机制等仍不十分明确。改变肠道病毒的组织靶向性、增加其安全性及溶瘤效能等分子水平上的进展将提高对肠道病毒作为溶瘤病毒的深入理解，促进肿瘤的防控。另外，还需进一步明确肠道溶瘤病毒与机体的相互作用，建立合适的动物模型，开发安全性与覆盖范围兼具的溶瘤制剂，开展更广泛的研究以优化肠道病毒的溶瘤治疗。
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