Treatment Strategy and Research Progress of Immune Microenvironment for Liver Metastasis of Non-small Cell Lung Cancer
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摘要:
肝脏是非小细胞肺癌转移扩散的常见部位，且肺癌肝转移患者的预后不良，或许与肝脏特异性微环境组成有关。多种病理生理因素的调控，包括肝脏免疫微环境、相关细胞、蛋白、信号分子及基因改变，都会对肺癌肝转移过程及后续的治疗策略产生影响。近年来，免疫检查点抑制剂治疗在晚期非小细胞肺癌患者中取得了突破性进展，但作为晚期肺癌的特殊人群，非小细胞肺癌肝转移患者具有免疫治疗较差的特点。本文对免疫微环境影响肝转移发生发展的相关机制加以综述，总结抗肿瘤免疫疗法在非小细胞肺癌肝转移中取得的成果及前景展望。
Abstract:Liver is the common site for metastasis and spread of non-small cell lung cancer (NSCLC). Lung cancer patients with liver metastasis have poor prognosis, which may be related to liver-specific microenvironment composition. The metastasis of lung cancer to the liver is regulated by various pathophysiological factors, including the liver immune microenvironment, related cells, proteins, signaling molecules, and gene changes. These factors will affect the consistent disease process and subsequent treatment strategies. Immune checkpoint inhibitors (ICIs) have made breakthroughs in treatment of patients with advanced NSCLC. However, NSCLC patients with liver metastasis, a unique population of advanced lung cancer, are characterized by poor immunotherapeutic effect. This paper reviews the related mechanisms of the immune microenvironment in affecting the occurrence and development of liver metastases and summarizes the achievements and prospects of anti-tumor immunotherapy in liver metastases of NSCLC.
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Key words:
- Non-small cell lung cancer /
- Liver metastasis /
- Immunotherapy /
- Immune microenvironment
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0 引言
胶质母细胞瘤（glioblastoma multiforme，GBM）为恶性程度最高的星形细胞瘤（属WHO分级的Ⅳ级）。临床上，由于该肿瘤呈浸润性快速生长，多数患者，颅内压迫症状严重，手术清除难度大。即便在手术配合放化疗治疗方案下，绝大多数GBM患者仍因肿瘤复发死亡，中位生存时间只有14~18月[1-2]。临床上，无论是原发或继发GBM患者，肿瘤的基因背景与生物学行为都具有不均一性，因此，每个患者都需进行个体化的治疗决策和预后判断。目前，应用于GBM的临床诊断技术和肿瘤监测手段仍比较单一（主要为影像学技术），存在缺陷，不利于GBM的个体化治疗决策，寻找新的更有效的检测手段迫在眉睫。
近年来，随着生物检测技术的发展，GBM患者血液中检测到肿瘤细胞已是不争的事实[3-4]，这些与GBM的复发密切相关的细胞称为循环肿瘤细胞（circulating tumor cells, CTCs），它们的检测也被誉为“循环活检”。尽管文献报道不多，CTCs的发现给GBM患者的诊治带来了新的希望，它在GBM的早期诊断、肿瘤复发风险评估和预后评估等方面具有潜在的临床应用价值，使GBM诊治的决策更加“有章可循”。本文就胶质母细胞瘤CTCs的一些研究进展综述如下。
1 胶质母细胞瘤CTCs概述
九十年代初，科学家们用免疫细胞化学和克隆形成实验技术检测到乳腺癌患者外周血中的肿瘤细胞后，CTCs的检测和应用逐渐受到重视[5]。迄今已有多项研究表明，GBM患者与一些肿瘤（乳腺癌、前列腺癌、结直肠癌等）患者一样，血液中可以检测到CTCs[3-4, 6-7]。但在外周血中，CTCs受血流剪应力、失巢凋亡和免疫细胞识别杀伤等因素的影响，绝大多数发生死亡[8]，这给CTCs的检测带来了极大的挑战。
有研究认为GBM患者中的CTCs来源于一群具有高度繁殖、自我更新、分化的能力的细胞群体，称为GBM肿瘤干细胞（glioblastoma stem cells, GSC）[8]；GSC具有较高的成瘤潜质，且能够通过神经上皮间质转换过程（glio-mesenchymal transition, GMT）[9]逃脱原发的肿瘤组织，由微脉管入侵循环系统，最后在远处或原发部位种植，完成肿瘤的转移和复发。肿瘤患者血液中幸存的CTCs不仅具有增殖、侵袭和迁移能力，而且具有极强的环境适应能力，对于放化疗具有一定的抵抗性，表现出明显的干细胞特性[10]。这种特性可解释GBM各种治疗效果不理想、易复发、预后极差的原因。
2 CTCs与GBM的复发
绝大多数GBM最终会复发。手术治疗很难做到完全清除肿瘤细胞，其目的更多是为了减轻瘤负荷、缓解症状、明确病理。GBM复发机制复杂，除了与肿瘤的分化程度、手术切除范围、放化疗敏感度等因素有关外，与进入循环的肿瘤细胞也有关，Macarthur等[6]在胶母CTCs的检测中发现，在术后化疗的GBM患者血液中，肿瘤细胞较术前明显减少，遗憾的是该研究未能对患者的预后进行统计分析。
GBM复发的机制有多种观点，有研究认为GBM肿瘤干细胞（GSC）是GBM复发的主要原因。GSC相邻的肿瘤细胞会通过旁分泌和细胞接触等方式抑制GSC，使GSC进入休眠状态。在特定的情况下，如手术、化疗、肿瘤细胞脱落入血等因素影响，使静止的GSC与周围肿瘤细胞隔开，增殖能力将会被重新激活。这种静止又被重新激活的GSC按激活部位的不同分为两类：（1）原发灶的GSC；（2）脱落入血的GSC——CTCs。它们都可能是导致GBM复发的主要因素[11-12]。
研究报道虽然显示GBM极少发生其他器官的转移（仅0.4%的GBM患者伴有肝脏、脾脏、肾脏及皮肤的转移）[13-14]，但是大多数GBM最终都会复发，其中约2/3复发区域位于原发肿瘤附近（≤2 cm），由原发灶的GSC激活所致。而远处复发（> 2 cm）约占1/6的复发性GBM，发生于对侧大脑半球、其他脑叶或幕下等[15]。一些观点认为，远处复发的GBM并非源于原发肿瘤，而是在放化疗或其他因素下诱导发生，属于新原发肿瘤。而一些研究持有不同的观点，认为GBM的复发起源于原发肿瘤，并提出远处复发的肿瘤与原发肿瘤的基因具有一定的相似性[16]。也就是说，CTCs是导致肿瘤在远处复发的原因，这也是复发肿瘤与原发肿瘤基因相似性的原因，放化疗则可能诱导了CTCs的发生。
3 胶质母细胞瘤CTCs检测技术进展
目前，CellSearch系统是美国食品药品监督管理局唯一批准用于临床检测CTCs的产品（主要针对乳腺癌及前列腺癌)[17]，它的应用主要基于CTCs特异的高表达的上皮分子相关抗原（如EpCAM、CK等）。但经过神经上皮间质转换过程（GMT）的胶质母细胞瘤CTCs，EpCAM、CK的表达缺失[18]，使CellSearch系统无法应用于胶质母细胞瘤CTCs与外周血细胞的分离，因此识别胶质母细胞瘤CTCs需要新的免疫分子。所以高敏感、高特异的辨识因子和检测手段标准化应用，是当下胶质母细胞瘤CTCs研究重点所在。
如何检测胶质母细胞瘤CTCs，科学家们设计多种方法。Müller等[3]曾采集141例GBM患者血液，与健康者血液对照，通过离心法富集血液中所有细胞，用胶质原纤维酸性蛋白（glial fibrillary acidic protein, GFAP）免疫染色的方法识别CTCs，结果显示GFAP阳性率为20.6%。而这些GFAP阳性的细胞呈现表皮生长因子受体（epidermal growth factor receptor, EGFR）基因的表达明显上调。Sullivan等[4]通过微流体技术——CTC-iChip富集87例GBM患者血液中的细胞，再用一组胶质瘤标志物（SOX2、tubulinbeta-3、EGFR、A2B5和c-Met）进行CTCs的识别，结果在27例GBM患者血液中发现了CTCs，还发现一些与侵袭性相关的基因（如SERPINE1、TGFB1、TGFBR2和vimentin等）在这些CTCs中高表达。
Macarthur等[6]使用物理离心法富集血细胞，然后用含人端粒酶反转录酶启动子和绿色荧光蛋白（green fluorescent protein, GFP）表达盒的腺病毒感染所得细胞，使细胞能在端粒酶反转录酶的作用下激活（GFP telomerase-based assay），结果发现11例患者中有8例（72%）为CTCs阳性，而在8例经放疗的高级别胶质瘤患者血液中仅1例（12%）CTCs阳性。Zhang等[7]用类似的方法（所选择的病毒不同）检测了290例肿瘤患者及178例正常人血液样本，肿瘤病例包括肺癌、结肠癌、胃癌、肝癌、胰腺癌及胶质瘤，其中CTCs阳性患者为219（75.5%）例，而在39胶质瘤患者中，CTCs阳性为23（59%）例。
4 CTCs应用于GBM的展望
CTCs是否存在于早期的GBM患者血液中目前仍有争议。理论上GBM自形成之后，便存在GMT特性，不断的尝试将自身细胞释放入血，并企图在其他环境下进行无性繁殖[19]。因此，CTCs检测理论上能更早于影像学发现GBM。而临床上占位明确的颅内肿瘤患者，很难对肿瘤进行准确的定性分级，影响GBM患者治疗方案的选择，进而影响了GBM患者的总体预后。因此早期的分类定性GBM，相当于术前肿瘤的活体检查，将会给临床的治疗决策和改善患者的预后带来巨大的收益。例如，在以往不同版本的颅内肿瘤治疗指南中，手术切除、联合放射和化学治疗是治疗GBM的总原则，未经手术的经验型化疗及放疗方案，常因错判治疗的敏感度而延误最佳治疗时期，不仅影响治疗效果，而且增加患者经济负担。而术前CTCs的检测可以在基因和细胞层面早期评估肿瘤恶性程度，使临床工作者更迅速地预知放疗和化疗个体方案对患者治疗的敏感度，更利于肿瘤的规范化、个体化治疗，提高患者疗效，延长总体生存时间，并改善生存质量。
5 小结
GBM由于极差的预后而受到广泛的关注，在手术、放化疗多种方案的结合下，预后仍不良，这是因为GBM的恶性程度高和临床上缺乏及时准确的检测手段。近年来，随着生物检测技术的发展，CTCs被证明存在于GBM患者血液中，它具有肿瘤干细胞特性，能够被多种生物标记检测到，但现有的检测技术仍未标准和规范化。
胶质母细胞瘤CTCs的发现让我们看到了新的希望：（1）CTCs有望较影像学更早更及时地发现肿瘤；（2）CTCs有望成为术前准确诊断肿瘤的手段，指导临床治疗工作；（3）CTCs有望成为评估肿瘤复发的关键指标。当下寻找高敏感度的CTCs免疫标志物、优化检测手段是胶质母细胞瘤CTCs检测研究的重难点，目前CTCs的临床价值仍需更大量的研究数据评估。
Competing interests: The authors declare that they have no competing interests.利益冲突声明：所有作者均声明不存在利益冲突。作者贡献：孙家齐：论文撰写王玉栋：论文审校 -
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