修回日期: 2012-11-07
接受日期: 2012-11-15
在线出版日期: 2012-11-28
肝癌是我国常见的恶性肿瘤之一, 因其恶性程度高, 易于复发和转移而被广泛关注. 肝癌的发生、发展及预后与机体的免疫功能密切相关, 肝癌患者一般免疫功能低下, 这也是肝癌复发和转移的重要因素. 目前, 肝癌的治疗多是以外科切除为基础的综合治疗, 但患者就诊时多属于中晚期, 错过了外科手术机会. 肝癌的介入治疗被认为是非外科治疗的首选方法. 介入治疗在破坏肿瘤组织的同时, 也促进了肿瘤细胞的凋亡, 特别是提高了细胞免疫功能, 增强机体抗肿瘤的免疫力, 免疫功能的提高可能起到抑制肿瘤复发和转移的作用. 本文就近年来国内外介入治疗对患者免疫功能的影响作一综述.
引文著录: 张功霖, 赵卫. 介入治疗肝癌对免疫功能影响的研究进展. 世界华人消化杂志 2012; 20(33): 3225-3230
Revised: November 7, 2012
Accepted: November 15, 2012
Published online: November 28, 2012
Liver cancer is a common highly malignant tumor in China, with a high rate of recurrence and metastasis. The body's immune function is closely related with the occurrence and development of liver cancer, and low immunological function is an important reason why hepatic carcinoma is hard to cure and tend to recur and metastasize. At present, surgery-based comprehensive therapy plays a dominant role in the treatment of hepatic carcinoma; however, the majority of patients had lost their opportunities for surgical treatment when a definitive diagnosis was established. Interventional therapy is regarded as the first choice of nonsurgical treatment for hepatic carcinoma. Interventional therapy can not only result in coagulative tumor necrosis but also promote apoptosis of tumor cells. The body's immune function can be enhanced to improve the anti-tumor ability by interventional therapy, especially the cellular immune function. As a result, the metastasis and recurrence of hepatic carcinoma may be inhibited. The purpose of this article is to review the progress in understanding the effect of interventional therapy for hepatic carcinoma on immune function.
- Citation: Zhang GL, Zhao W. Recent progress in understanding the effect of interventional therapy for hepatic carcinoma on immune function. Shijie Huaren Xiaohua Zazhi 2012; 20(33): 3225-3230
- URL: https://www.wjgnet.com/1009-3079/full/v20/i33/3225.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v20.i33.3225
肝癌是常见的恶性肿瘤之一, 传统治疗以外科手术为主, 但患者就诊时大多数已为中晚期, 错过了手术机会. 介入治疗是治疗不可手术切除肝癌的首选治疗方法, 在治疗肝癌的同时提高了患者的免疫功能, 有利于控制肿瘤的复发与转移. 本文就介入治疗肝癌对患者免疫功能的影响作一综述.
机体抗肿瘤免疫以细胞免疫为主, 主要的免疫细胞为T淋巴细胞、自然杀伤细胞(natural killer cell, NK)、特异性细胞毒T细胞(cytotoxic T-lymphocyte, CTL), 以上细胞可以特异性识别肿瘤抗原, 刺激机体产生抗肿瘤效应细胞的增殖和分化, 并分泌多种细胞因子, 引起抗肿瘤免疫反应. T细胞分为Thl、Th2两个亚群, 其可分泌不同的免疫因子. Thl主要分泌白介素2(interleukin-2, IL-2)、干扰素γ(interferon-γ, IFN-γ)、肿瘤坏死因子-α(tunmor necros factor-α, TNF-α); Th2主要分泌IL-4、IL-10. NK细胞则对各种肿瘤细胞具有直接杀伤作用, 并且对血行转移的肿瘤细胞产生较强的杀伤作用, 在抑制肿瘤的转移方面起到积极作用. CD4+细胞是机体免疫应答的主要细胞, 其分泌的细胞因子可调节抗肿瘤免疫反应; CD8+细胞分泌的抑制性T淋巴细胞因子, 发挥特异性免疫抑制作用. 肝癌患者外周血抗肿瘤细胞及细胞因子情况: (1)肝癌患者外周血中CD4+、CD4+/CD8+比值、NK细胞数量明显下降, CD8+细胞数量明显增加, 均提示肝癌患者存在免疫抑制状态; (2)CD4+CD25+Treg细胞是最重要的免疫抑制细胞[1], 通过抑制 CD4+CD25+、CD8+CD25+T细胞、NK细胞的增殖及IL-2的分泌功能, 抑制CD8+记忆性T细胞的反应力, 降低抗原提呈效率[2,3]. 另有研究提示肝癌患者CD4+CD25+T细胞比例明显高于正常人群, 而淋巴细胞总数偏低, 同样提示肝癌患者存在不同程度的免疫抑制[4,5]. CD4+CD25+T细胞的表达与肝癌TNM分期显著相关, TNM分期越晚, CD4+CD25+T细胞的表达越高, 患者预后越差[6]; (3)肝癌患者外周血中Th1型细胞因子IL-2、IFN-γ的含量均降低, Th2型细胞因子IL-4、IL-10的含量均增高, 并存在Th1/Th2漂移现象, 使外周血中Th2型细胞占优势, 抑制了Th1型细胞抗肿瘤免疫效应[7]; (4)肝癌患者肿瘤组织内外的NK细胞、T细胞及巨噬细胞浸润均降低, 且外周血清中SIL-2R水平也明显升高[8].
经肝动脉化疗栓塞(transcatheter arterial chemoembolization, TACE)是不可手术切除中晚期肝癌的首选治疗方法之一[9], TACE在促进肿瘤坏死的同时也造成机体的免疫功能抑制, 尤其是化疗药物的不良反应会造成机体免疫抑制, 这会促进肿瘤的复发和转移. 单纯行TACE治疗肝癌, 对延长患者的生存期方面仍存在争议, 故目前肝癌的介入治疗多是以TACE为基础的综合介入治疗[10]. 既往TACE治疗肝癌所使用的化疗药物剂量较大, 化疗药物全身不良反应较大, 对机体的免疫抑制作用也较强; 目前TACE治疗时所使用的化疗药物使用剂量日趋规范, 在减少剂量的同时并没有影响TACE治疗肝癌的疗效, 这使得化疗药物全身的不良反应较之前明显降低, 免疫抑制作用也明显减轻; TACE治疗肝癌后随着肿瘤的坏死, 肿瘤细胞分泌的免疫抑制因子减少, 对机体的免疫抑制作用减轻, 机体免疫功能在TACE术后1 mo可逐渐得到恢复, 故TACE治疗肝癌后患者的免疫功能降低是暂时的[11].
物理消融主要包括射频消融(radiofrequency ablation, RFA)、微波消融(microwave coagulation treatment, MCT)、高聚焦超声消融(high intensity focused ultrasound, HIFU)、冷冻消融(cryoablation)等. 以上方法均是通过高温或低温的方法使肿瘤组织发生凝固性坏死, 以达到治疗肝癌的目的. 据国内外文献综合分析, 物理消融治疗肝癌对患者免疫功能影响的作用机制主要有: (1)肿瘤坏死组织作为特异性抗原活化抗原提呈细胞, 诱导肿瘤特异性淋巴细胞反应, 改善机体的免疫耐受状态; (2)肿瘤细胞坏死后所分泌的免疫抑制因子减少, 使肝癌患者的免疫抑制状态减轻; (3)高水平的甲胎蛋白(alpha fetoprotein, AFP)对机体有免疫抑制作用, 物理消融后AFP明显下降, 可减轻肿瘤对机体的免疫抑制作用; (4)肿瘤细胞灭活后产生大量热休克蛋白(heat shock protein, HSP), 残存肿瘤组织内的HSP明显增多[12,13], HSP可诱发机体的抗肿瘤免疫功能, 参与肿瘤抗原提呈和激发T细胞介导的细胞免疫反应[14,15]; (5)肿瘤局部造成炎性环境, 有利于抗原提呈细胞聚集, 诱导抗肿瘤免疫作用.
常用物理消融治疗肝癌的临床研究: (1) RFA治疗肝癌后患者抗肿瘤免疫力明显增强, T细胞Th1亚群分泌的细胞因子(IL-2、TNF-α)明显升高, Th2亚群分泌的细胞因子(IL-4、IL-10)明显下降[16]. 王艳滨等[17]用RFA治疗26例是肝细胞癌(hepatocellular carcinoma, HCC)患者后, 血清IL-4、IL-10含量较治疗前明显下降, IL-2和IFN-γ含量均增高, NK细胞数量也较术前有所升高. 研究表明, NK细胞可分泌的IFN-γ和IL-2能增强NK细胞的杀伤活性并诱导其活化与增殖, 进一步增强机体抗肿瘤的细胞免疫功能[18], 也有RFA治疗肝癌后IL-2明显升高和slL-2R明显降低的报道[19]; (2)MCT消融肝癌后CD4+、CD4+/CD8+、NK细胞数目明显上升, CD8+细胞明显降低, 与正常健康者相比, 体液免疫无明显差异, 虽然术后IgG、IgM、IgA含量较术前均有不同程度的升高, 但无显著差异性, 提示MCT对肝癌患者体液免疫功能影响较小[20]; (3)HIFU是近年来发展起来利用超声波的可视性、软组织穿透性和可聚焦性物理特点治疗实质性肿瘤的新技术. HIFU治疗是一种非侵入性治疗方法[21,22], 具有对肿瘤周围组织损伤小或者无损伤的特点, 可有效避免经皮介入技术所引起的并发症, 如RFA、MCT等引起的出血、感染、针道转移. HIFU通过高温使肿瘤组织发生不可逆性坏死[23], 肿瘤坏死组织可作为抗原刺激机体产生特异性抗肿瘤的免疫力[24,25]; (4)冷冻消融在治疗肝癌的同时, 肿瘤坏死组织释放肿瘤抗原, 刺激机体免疫应答, 产生抗肿瘤的免疫力. 冷冻治疗后Treg细胞比例可轻度下降, CD4+、CD4+/CD8+、NK细胞明显升高, CD8+细胞降低, 均具有显著性差异[26].
放射性粒子植入是内放疗, 不但没有外放疗引起的并发症, 并且提高了局部放疗效果. 放射性粒子植入可提高肝癌患者的免疫功能, 其机制主要有: (1)内放疗后肿瘤细胞坏死可减少肿瘤产生的免疫抑制因子, 减轻了机体的免疫抑制状态; (2)治疗后AFP明显下降, 可解除AFP对机体免疫功能的抑制作用[27,28]; (3)内放疗后炎症介导因子激活免疫系统细胞, 最终激活适应性免疫反应, 起到免疫调节作用[29]; (4)放疗后产生放疗特异性蛋白, 活化淋巴细胞释放细胞因子, 提高机体抗肿瘤的免疫力. 目前有关放射性粒子植入可提高肝癌患者免疫功能方面的研究较少, 研究的最终目的是要延长患者的生存期, 故需要大量的临床随机对照研究来支持这一观点[30].
因肝癌的恶性程度高, 较早即可发生转移, 肝癌的这一生物学特性决定了肝癌的治疗用单一方法难以取得满意的疗效, 故目前对手术不可切除肝癌的治疗多是以TACE为主的综合介入治疗. TACE联合其他方法综合治疗肝癌的依据有: (1)联合物理消融治疗, TACE可使肿瘤大部分血供被阻断, 可减少RFA、HIFU等物理消融时热量随血流的丢失, 提高物理消融的疗效. 物理消融可以治疗TACE栓塞后的残存病灶, 其热效应增加细胞的通透性, 可使化疗药物进入肿瘤细胞内, 提高了化疗药物的疗效, 故TACE联合物理消融可发挥优势互补的作用[31,32]; (2)TACE联合分子靶向药物, TACE术后残存病灶仍可复发, 且术后极易促进肿瘤周边侧枝循环的建立. TACE联合分子靶向药物治疗肝癌, 可有效抑制肿瘤血管的生成, 起到抑制肿瘤复发与转移的作用[33,34]. 以下为TACE为主的常用综合介入治疗方法治疗肝癌后患者免疫功能变化的研究.
HCC非手术治疗的首选, 因肝癌经过TACE治疗后存在肿瘤坏死不彻底、易复发和转移的特点. 单纯TACE治疗肝癌病灶完全坏死率低, 且化疗药物对机体免疫功能的抑制作用对患者预后产生不良影响. 冷冻消融是采用超低温直接杀伤肿瘤细胞的方法, 短时间内可降低肿瘤负荷, 在一定程度上激活了机体抗肿瘤免疫反应[35]. 冷冻消融后, 肿瘤坏死细胞碎片被吸收后, 形成肿瘤细胞特异性抗原, 刺激CTL和树突状细胞增殖, 激发机体产生特异性抗肿瘤免疫, 进一步抑制肿瘤的复发与转移[36]. TACE联合冷冻消融治疗肝癌后患者外周血中CD3+、CD4+、CD4+/CD8+比值上升, CD8+和Treg细胞数目及AFP下降明显, 均明显优于单纯TACE治疗[37].
Li等[38]经临床随机对照试验证明TACE联合HIFU治疗肝癌的坏死率和中位生存期明显优于单独TACE. HIFU治疗肿瘤后, 坏死组织为机体提供了自体灭活肿瘤疫苗, 成为特异性抗原刺激机体产生免疫应答, HIFU的高温效应可解除肿瘤细胞分泌的免疫抑制因子对机体免疫的抑制作用[39,40]. 单纯HIFU与单纯TACE治疗肝癌后, HIFU治疗肿瘤可使外周血中CD4+、CD4+/CD8+、NK细胞明显升高, 而单纯TACE治疗后上述细胞短期内会出现轻度下降[41]. HIFU治疗肝癌后提高了患者抗肿瘤的免疫力. 由此推断, HIFU治疗肝癌引起的免疫功能的提高可以对抗由TACE治疗所使用的化疗药物带来的对机体的免疫抑制作用, 但目前缺少TACE联合HIFU与单纯HIFU治疗肝癌方面疫功能方面的对比研究.
RFA单独治疗直径为2-5 cm的肝癌即可达到满意的疗效[42], 但大肝癌需要TACE联合RFA才能达到治疗目的[43]. RFA产生的高温能使肝肿瘤组织发生凝固性坏死, 坏死组织作为抗原能够产生持续性的局部炎症反应, 活化抗原提呈细胞, 诱导肿瘤特异性T淋巴细胞反应, 可改善机体抗肿瘤免疫耐受状态[44]. Osada等[45]报道, RFA治疗肝癌后能观察到非治疗区域肿瘤坏死, 这种现象的出现和IL-10降低, TNF-α和Th1/Th2比值升高有关. Napoletano等[46]报道, RFA治疗转移性肝癌能够诱导CD62L(+)T细胞从循环进入局部组织, 增强机体的抗肿瘤细胞免疫功能, 但治疗HCC未观察到类似现象.
索拉菲尼是多激酶抑制剂, 具有双重抗肿瘤作用即直接抑制肿瘤增殖和抑制肿瘤血管生成的作用[47], 还具有提高肝癌患者免疫功能的作用. Strebel等[48]提出TACE治疗肿瘤后造成缺氧环境, 诱导血管内皮细胞生长因子过度表达、新生血管生成, 肿瘤易出现复发与转移, TACE联合索拉非尼治疗肝癌可有效抑制肿瘤血管再生, 减少肿瘤的复发和转移, 提高肝癌的治疗效果. 动物实验证明, 索拉非尼增强机体免疫功能的作用机制是索拉非尼可降低肝癌患者外周血中免疫抑制细胞的数量, 起到免疫调节作用[49]. 目前有关索拉非尼增强肝癌患者免疫功能的研究较少, 故索拉菲尼提高肝癌患者免疫功能的具体机制有待进一步研究.
目前有关介入治疗对患者免疫功能影响方面的实验及临床研究已取得一定成果, 并且肝癌的免疫治疗也有较好的研究基础[50,51], 但缺乏临床循证医学的有力证据证明疗效或效价比, 实际上这也是本文的不足之处. 随着多种介入治疗方法在临床的广泛应用, 介入治疗肝癌免疫功能变化的机制将更加明确, 有望在杀灭残癌细胞, 降低术后复发率, 提高远期疗效方面发挥积极作用, 并为肝癌的免疫治疗提供有力的理论依据.
外科切除是治疗肝癌的首选方案, 但患者就诊时多属中晚期, 错过了手术机会. 介入治疗是不可手术中晚期肝癌的首选治疗方法, 并能提高患者的免疫功能. 免疫功能的提高有望在控制肿瘤的复发、转移方面起到积极作用, 但目前有关介入治疗肝癌后对免疫功能影响的确切机制仍未明确.
麻勇, 副研究员, 哈尔滨医科大学附属第一医院肝脏外科
目前针对介入治疗肝癌对患者免疫功能影响机制, 以及细胞免疫的研究已成为热点、重点.
小样本的动物实验和临床研究已证实, 介入治疗肝癌可提高患者的细胞免疫功能.
本文对介入治疗肝癌对免疫功能影响机制的研究进展进行综述, 以期为广大读者提供更大的思考空间.
本文对介入治疗肝癌对患者免疫功能影响机制的研究进展进行综述, 为相关研究提供方向和思路.
本文深入探讨介入治疗肝癌对免疫功能的影响, 比较详实地对当前该领域的研究作以客观综述, 具有较好的借鉴价值.
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