Research progress of tertiary lymphoid structures in evaluation and treatment of gastric cancer and other tumors
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摘要:
三级淋巴结构（TLSs）作为肿瘤微环境的关键组成部分，近年来在肿瘤研究领域备受关注。TLSs由多种免疫细胞构成，在慢性炎症刺激下形成，成熟过程分为不同阶段。其通过模拟次级淋巴器官功能，产生适应性免疫应答发挥抗肿瘤作用。在胃癌预后方面，TLSs的细胞成分、空间分布及其与其他指标联合，均有助于预测患者预后。同时，TLSs评分系统有望成为评估免疫治疗效果的指标。诱导TLSs形成的治疗策略在动物模型中已取得一定成果，但仍需关注其潜在治疗风险。笔者聚焦于TLSs形成和成熟过程、抗肿瘤作用机制及其在胃癌及多种肿瘤中的预后评估和免疫治疗预测中的价值，以及诱导TLSs形成的治疗策略。
Abstract:Tertiary lymphoid structures (TLSs), as a crucial component of the tumor micro-environment, have attracted significant attention in the field of tumor research in recent years. TLSs are composed of multiple immune cells and formed under the stimulation of chronic inflammation, with their maturation process divided into different stages. They exert anti-tumor effects by mimic-king the functions of secondary lymphoid organs and generating adaptive immune responses. In terms of the prognosis of gastric cancer, the cell composition, spatial distribution of TLSs, and their combination with other indicators are all helpful in predicting the prognosis of patients. Meanwhile, the TLSs scoring system is expected to become an index for evaluating the efficacy of immuno-therapy. Treatment strategies for inducing TLSs formation have achieved certain results in animal models, but potential treatment risks require attention. The authors elaborate on formation and maturation process of TLSs, anti-tumor mechanism, value in prognostic assessment of gastric cancer and multiple tumors, prediction of immunotherapy, as well as treatment strategies for inducing the formation of TLSs.
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三级淋巴结构（tertiary lymphoid structures，TLSs）是在缺乏规范淋巴器官组织部位中后天形成的有组织的免疫细胞聚集体。TLSs在解剖学上类似于次级淋巴器官（secondary lymphoid organ，SLO），如淋巴结、脾、扁桃体、派尔集合淋巴结和黏膜相关淋巴组织，但诱导TLSs形成提供刺激的细胞和信号传递方式并不完全相同[1-2]。TLSs在生理条件下不存在，而存在于慢性炎症背景下，例如自身免疫性疾病、慢性感染和肿瘤中[3-5]。在大多数肿瘤中，TLSs的存在与患者预后和免疫治疗的效果相关[6-7]。但肿瘤中TLSs形成的驱动因素以及这些结构对肿瘤内免疫应答的贡献仍不完全清楚。胃癌是全世界发病率及死亡率均位居第5的常见恶性肿瘤，发病例数约为97万/年，死亡例数约为66万/年[8]。有研究结果显示：TLSs与胃癌患者的预后和辅助治疗的效果密切相关[9]。TLSs在胃癌相关的肿瘤微环境中可能起着至关重要的作用。因此，深入了解诱导胃癌相关TLSs形成的分子机制以及其对肿瘤特异性免疫产生的影响，有助于制订针对TLSs的治疗策略，并基于TLSs预测胃癌患者的预后。笔者综述TLSs在胃癌等多种肿瘤预后与治疗策略中的研究进展。
一. 肿瘤相关TLSs的形成和成熟过程
随着病理学技术的发展和肿瘤微环境研究的深入，TLSs逐渐被发现，在不同肿瘤类型中，甚至在同一肿瘤的不同区域，TLSs的构成和类型可能有所不同。TLSs主要由B细胞、T细胞、树突状细胞、滤泡树突状细胞和高内皮微静脉（high endothelial venule，HEV）组成。在持续的慢性炎症环境中，SLO以外的免疫细胞受到炎症信号刺激，导致在非常规淋巴组织中形成TLSs。某些病理条件下，如抗原呈递细胞，识别肿瘤细胞暴露的抗原，将其递呈给适应性免疫细胞，导致免疫细胞激活和细胞因子分泌[10]。这些被激活的淋巴细胞表达淋巴毒素-α，与基质细胞上表达的相应受体（淋巴毒素-β受体）相互作用。淋巴毒素-α亦可诱导多种趋化因子的表达，包括趋化因子（C-C基序）配体19和21、趋化因子（C-X-C基序）配体12和13[11]。趋化因子（C-X-C基序）配体13和IL-7可将淋巴组织诱导细胞招募到病变部位[12]。其中的淋巴毒素-α1β2与淋巴毒素-β受体结合，可能促进VEGFA和VEGFC的分泌，从而诱导HEV的形成[13]。除了上述依赖淋巴组织诱导细胞的TLSs形成途径外，趋化因子配体21和19还可诱导T细胞淋巴毒素-α1β2的表达，趋化因子配体13刺激B细胞淋巴毒素-α1β2的分泌，两者均可通过淋巴毒素-β受体信号依赖途径从附近的HEV招募淋巴细胞进入TLSs[14-15]。其他免疫细胞，如巨噬细胞、内皮细胞、成纤维细胞、骨髓间充质干细胞和脂肪细胞也在TLSs的形成和成熟过程中发挥重要作用[16]。
依据是否存在滤泡树突状细胞和B细胞的分化情况，肿瘤中的TLSs成熟度可分为3个发展阶段：（1）聚集型，密集淋巴细胞簇，但不含滤泡树突状细胞。（2）初级滤泡型：含有滤泡树突状细胞的淋巴细胞簇，但不含生发中心。（3）次级滤泡型：含有生发中心与滤泡树突状细胞的淋巴细胞簇[17]。在胃癌中可以观察到3种不同成熟度水平的TLSs，其中聚集型TLSs的比例最高[18-19]。除了胃癌，TLSs在非转移性结直肠癌中也存在不同的成熟阶段[20]。Zhang等[21]的研究结果显示：在非功能性胰腺神经内分泌肿瘤中，CD4+和CD8+ T细胞主要分布在小叶旁皮质，且CD4+ T细胞较CD8+ T细胞更具浸润性。CD20+ B细胞则主要分布在滤泡中心，CD11c+树突状细胞和CD45RO+记忆性T细胞主要分布在T细胞区，部分散在分布于滤泡中心。调节性T细胞在TLSs和肿瘤组织中均很少见[22-23]。Park等[24]的研究结果显示：特征性表达外周淋巴结地址素蛋白和血管地址素蛋白的HEV位于胃癌TLSs周围。对于TLSs的检测，HE染色切片在不同病理学专家中重复性较差，因此，采用基因芯片和单细胞图谱来检测TLSs[25]。Coppola等[26]的研究展示了12种趋化因子基因信号在TLSs检测中的应用，并通过免疫基因芯片图谱鉴定了人类原发结直肠癌中独特的异位淋巴结样结构。Jia等[27]的研究通过单细胞图谱检测TLSs的细胞组成，提出NK T细胞主要存在于伴有成熟TLSs的胃癌组织中。由于新的TLSs检测技术的出现，越来越多的手段被用于评估TLSs，有助于更好识别胃癌相关TLSs。
二. 肿瘤相关TLSs的抗肿瘤作用机制
由于TLSs在解剖学上与SLO相似，因此，TLSs在炎症组织部位展现与SLO相似的功能。SLO通过提供来自组织的抗原呈递细胞和来自血液的幼稚淋巴细胞的接触环境，从而产生适应性免疫应答[28-29]。TLSs亦可产生或增强适应性免疫反应，TLSs中B细胞可以产生与疾病相关的抗体，这些抗体可以标记表达抗原的细胞并参与补体介导的对肿瘤细胞的裂解或抗体依赖的细胞毒性作用[30]。TLSs和SLO在结构上最大的区别是TLSs周围无膜或有少量膜，这为免疫细胞的移动提供了更方便的场所[31]。TLSs中的各种淋巴细胞和免疫球蛋白效应分子可更快地通过HEV或在淋巴组织和周围组织之间自由移动，以发挥相应的抗肿瘤免疫反应[28]。
TLSs是淋巴细胞诱导和成熟的场所，也为滤泡树突状细胞提供生存场所。滤泡树突状细胞是一种重要的抗原呈递细胞，能将暴露的肿瘤特异性抗原和肿瘤相关抗原呈递给T细胞和B细胞，使其成为功能亚群。TLSs还为效应T细胞和效应B细胞发挥抗肿瘤免疫反应提供了必要场所。当正常T细胞和B细胞成熟时，树突状细胞会及时向其呈递抗原，促进免疫球蛋白的产生和效应性T细胞的应答。此外，TLSs中的B细胞也可以作为抗原呈递细胞，向CD8+ T细胞呈递抗原，进一步增强其免疫反应[32]。因此，TLSs被认为是一个局部免疫和抗肿瘤的“微战场”，为抗肿瘤免疫提供就近位置。
三. TLSs对胃癌等多种肿瘤的预后价值
在多数恶性肿瘤中，TLSs与良好预后相关，且TLSs的预后价值通常独立于TNM分期[10]。TLSs密度及其所包含的细胞已显示与多种类型肿瘤患者预后相关[33-34]。基于TLSs在肿瘤免疫微环境里抗肿瘤免疫反应中的重要性，越来越多的研究评估TLSs在预测胃癌患者预后中的价值。Yu等[35]的研究结果显示：高TLSs密度与胃癌患者的总生存期和无病生存期的延长有关。肿瘤周围TLSs的数量不仅影响患者预后，而且TLSs的细胞成分与空间分布也在评估肿瘤患者预后中发挥重要作用。
一 TLSs细胞成分与肿瘤预后的关系
肿瘤浸润淋巴细胞的成分构成对抑制肿瘤进展至关重要，TLSs是其重要来源[36]。Li等[23]的研究结果显示：TLSs可作为胃癌患者的独立预后因素，而TLSs联合肿瘤浸润淋巴细胞优于单独使用TLSs对胃癌患者进行生存预测。此外，TLSs中的CD8+ T细胞与胃癌患者年龄、组织学分级和病理学T分期与N分期显著相关。Park等[24]的研究结果显示：HEV高的胃癌患者部分免疫细胞亚群增加，包括树突状细胞、CD8细胞毒性T细胞和CD4辅助性T细胞。HEV高的胃癌患者总生存时间和无复发生存时间更长。Yamaguchi等[37]研究分析67例Ⅱ期或Ⅲ期结直肠癌患者的术后病理学切片，其中58例患者肿瘤组织中证实存在TLSs，包括生发中心B细胞，滤泡树突状细胞，辅助性T细胞、B细胞，细胞毒性T细胞和巨噬细胞。复发患者的辅助性T细胞和巨噬细胞显著高于未复发患者。因此，TLSs中的细胞成分影响其在预测患者预后中的价值，这取决于抗肿瘤亚群和免疫抑制性亚群之间的平衡。
二 TLSs的空间分布与肿瘤预后的关系
Calderaro等[38]的研究结果显示：肝细胞癌患者肿瘤内的TLSs与早期复发风险低（术后2年内）有关，与晚期（术后 > 2年）复发风险无关；而在癌旁组织中的TLSs对早期和晚期复发无预测价值，这凸显了TLSs位置对患者预后的预测价值。位于非肿瘤肝脏的TLSs只对局部炎症起作用，而位于肿瘤核心区的TLSs真正反映了有效的抗肿瘤免疫。Ding等[39]的研究结果也显示：肝细胞-胆管细胞癌肿瘤内TLSs密度高与生存时间延长相关，而癌旁组织中TLSs密度高则提示预后较差。肿瘤周围高TLSs密度与低肿瘤间质百分比是非转移性结直肠癌患者良好预后的独立影响因素[20]。在非功能性胰腺神经内分泌肿瘤患者的术后病理学标本中也检测到位于肿瘤组织周围的TLSs，而该研究结果显示：TLSs的存在提示患者总生存时间和无复发生存时间更长，但TLSs的数量无预后意义[21]。这都提示肿瘤患者其病灶中具有邻近肿瘤组织的TLSs会有更好的预后及生存。
三 TLSs与其他指标联合对肿瘤预后的预测作用
肿瘤患者的预后因素是多方面的，单一依靠TLSs并不能准确预测患者的预后。Guner和Kim[40]的研究结果显示：中性粒细胞和淋巴细胞比值与各种肿瘤的不良预后有关。这主要是因为随着肿瘤的生长，由肿瘤细胞或周围组织引起的非特异性炎症反应会增加外周血中性粒细胞计数并减少淋巴细胞计数[41]。Yamakoshi等[42]的研究基于胃癌患者的中性粒细胞与淋巴细胞比值及TLSs密度进行分层分析，结果显示：低中性粒细胞与淋巴细胞比值联合高密度TLSs组胃癌患者预后明显优于其他组。除了肿瘤细胞生长所导致的肿瘤微环境变化，高肿瘤基质百分比与预后不良和免疫微环境抑制相关[43]。Wang等[20]的研究结果显示：在结肠肿瘤中，TLSs密度高与高肿瘤基质百分比低的患者有更好的生存获益，且包括TLSs、高肿瘤基质百分比及TNM分期的列线图可更准确地判断非转移性结直肠癌患者预后。可见，TLSs联合其他指标会更有助于预测肿瘤患者的预后。
四 TLSs在肿瘤免疫治疗中的预测价值
目前，肿瘤的辅助治疗包括放射治疗、化疗、靶向治疗和免疫治疗，均对肿瘤微环境中的免疫细胞产生影响。近年来，免疫检查点阻断疗法为肿瘤治疗提供了一种新的途径。然而并非胃癌患者均可从免疫检查点阻断疗法中获益[44-46]。考虑到TLSs塑造个体肿瘤微环境特征的重要作用，Jiang等[19]构建TLSs评分体系评估PD-1阻断治疗胃癌患者疗效。其研究结果显示：13例胃癌患者在接受PD-1阻断治疗后具有更高的TLSs评分，这表明TLSs的产生可能发生在免疫治疗后，也提示TLSs有望作为免疫治疗良好反应的生物标志物。在乳腺癌中，高水平的肿瘤浸润淋巴细胞和TLSs与免疫检查点的高表达有关，提示TLSs也可预测乳腺癌免疫治疗的效果[47]。因此，TLSs评分系统有望作为预测肿瘤患者免疫治疗效果的指标。
四. 诱导TLSs形成的胃癌治疗策略
鉴于TLSs与疾病结局的相关性，有研究提出一种创新的免疫治疗策略即诱导肿瘤微环境中TLSs的形成。通过组织特异性表达TLSs相关的细胞因子和趋化因子局部诱导TLSs的可行性已在动物模型中得到证实[14,48-51]。在胃癌的临床前小鼠模型（gp130F/F）中可以观察到新形成的肿瘤相关TLSs，过度活跃的gp130-STAT3信号传导可能与新生淋巴组织密切相关[52]。此外，表达IL-7和CCL19的抗原受体嵌合-T细胞，可以在肿瘤组织中形成TLSs[53]。在乳腺癌与神经内分泌胰腺癌小鼠模型中，PD-L1与抗血管生成药物联合治疗导致肿瘤组织内的血管转化为HEV，随后形成TLSs[54-55]。在不同类型的疫苗接种后也可观察到TLSs诱导形成。例如，在高度宫颈上皮内瘤变患者中，接种人乳头瘤病毒癌蛋白疫苗后的消退病变中观察到TLSs形成[56]。免疫治疗可以增加T细胞的浸润进而增加TLSs的形成，从而达到更好的抗肿瘤免疫效果[57]。有Ⅱ期临床试验结果显示：20例非小细胞肺癌患者接受新辅助抗PD-1治疗，术后标本检查中发现对治疗有反应的患者体内TLSs发生率增加；对治疗无应答患者的标本中，TLSs很少形成或未形成[58]。新辅助化疗也能促进TLSs的再生。非小细胞肺癌以及与抗原呈递细胞突变相关的肝母细胞瘤患者新辅助化疗后均观察到TLSs生成[59-60]。值得注意的是，在鳞状细胞肺癌患者中获得了相同结果，其中新辅助化疗导致TLSs成熟受损和生发中心丢失[61]。因此，相关的信号通路、治疗细胞、免疫检查点抑制剂、肿瘤疫苗和新辅助化疗都可能驱动TLSs的产生，从而在肿瘤治疗中产生更好的抗肿瘤免疫应答。
尽管诱导或增强TLSs功能可能改善肿瘤控制，但此类干预可能同时增强其他组织部位的反应性T细胞和B细胞应答。自身免疫反应是免疫检查点阻断疗法治疗后的主要毒性类型，免疫相关不良事件类似于自身免疫性疾病中常见的炎症过程，包括关节炎、肌炎、甲状腺炎、血管炎和结肠炎[62]。因此，诱导或加强TLSs功能不仅增强了抗肿瘤反应，还促进了自身反应性T细胞和B细胞扩增，因此需要仔细评估这些方法的风险效益比。
五. 小结
TLSs在肿瘤中的预后和预测价值，激发了研究人员对这些结构作为抗肿瘤免疫的兴趣。根据现有证据，TLSs有助于肿瘤特异性免疫应答。胃癌相关的TLSs存在于肿瘤局部区域，是肿瘤微环境中抗肿瘤免疫的重要组成部分。TLSs的存在通常是胃癌预后良好的指标。进一步研究TLSs在胃癌中的形成，将有助于更好地了解TLSs在肿瘤免疫中的作用。此外，随着辅助治疗和免疫治疗应用的增多，尤其是在辅助治疗后转移淋巴结数目可能减少甚至消失的情况下，TLSs是否会成为局部免疫反应的部位亟待阐明。基于TLSs中复杂的细胞成分，如何在TLSs中存在抑制性免疫亚群的情况下发挥适当的抗肿瘤免疫反应也至关重要。针对TLSs的治疗已在动物模型中提供有希望的结果，尚需在未来转化为临床试验进一步验证。
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