修回日期: 2026-03-20
接受日期: 2026-03-25
在线出版日期: 2026-03-28
肿瘤免疫微环境是一个高度复杂的生态系统, 肝细胞癌(hepatocellular carcinoma, HCC)中肝癌细胞、免疫细胞(肿瘤相关巨噬细胞、T细胞和骨髓来源抑制细胞、NK细胞等)、细胞因子(趋化因子、转化生长因子β、白细胞介素-10等)、基质(纤维连接蛋白、透明质酸、胶原蛋白等)和Wnt/β-catenin信号通路等相互作用、相互影响形成HCC特殊免疫微环境, 肿瘤局部免疫微环境异常使机体不能正常发挥免疫防御反应, 导致肿瘤免疫逃逸、转移和复发, 阐明肝癌细胞、免疫细胞、基质和分子网络相互作用在HCC复发转移中作用机制, 采取针对性措施纠正肿瘤免疫微环境异常, 通过激活特异性有效的抗肿瘤免疫反应, 是显著降低HCC复发转移, 延长HCC患者生存期, 改善HCC患者预后的关键.
核心提要: 肝癌细胞、肿瘤相关巨噬细胞、T细胞和骨髓来源抑制细胞等免疫细胞、细胞因子、基质等相互作用、相互影响形成肝细胞癌特殊免疫微环境, 促使肝癌细胞免疫逃逸、侵袭和迁移.
引文著录: 盛霞, 秦建民. 肿瘤免疫微环境在肝细胞癌复发转移中生物学作用. 世界华人消化杂志 2026; 34(3): 190-206
Revised: March 20, 2026
Accepted: March 25, 2026
Published online: March 28, 2026
The tumor immune microenvironment is a highly complex ecosystem. The interactions among hepatoma cells, immune cells (e.g., tumor-associated macrophages, T cells, bone marrow-derived suppressor cells, and NK cells), cytokines (e.g., chemokines, transforming growth factor-beta, and interleukin-10), extracellular matrix components (e.g., fibronectin, hyaluronic acid, and collagen) and the Wnt/β-catenin signaling pathway collectively define the specific immune microenvironment of hepatocellular carcinoma (HCC). Abnormalities in the local tumor immune microenvironment prevent the body from functioning normally in immune defense responses, leading to tumor immune escape, metastasis, and recurrence. Clarifying the mechanism of the interaction among hepatoma cells, immune cells, matrix components, and molecular networks in the recurrence and metastasis of HCC, and taking targeted measures to correct the abnormal tumor immune microenvironment by activating specific and effective anti-tumor immune responses, is key to significantly reducing recurrence and metastasis, prolonging survival, and improving prognosis in patients with HCC.
- Citation: Sheng X, Qin JM. The tumor immune microenvironment in hepatocellular carcinoma: Its biological role in recurrence and metastasis. Shijie Huaren Xiaohua Zazhi 2026; 34(3): 190-206
- URL: https://www.wjgnet.com/1009-3079/full/v34/i3/190.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v34.i3.190
肿瘤免疫微环境(tumor immune microenvironment, TIME)是肿瘤在环境选择压力下形成异质性的重要因素, 是一个高度复杂的生态系统, 肿瘤细胞与免疫细胞在时间、空间维度动态互相作用, 产生时空异质性, 在肿瘤时空演化的动态过程中, 肿瘤内在因素与微环境外在因素相互作用, 导致肿瘤基因组和表观组改变, 显著影响肿瘤浸润淋巴细胞(tumor-infiltrating lymphocytes, TILs)丰度和活性, 而免疫浸润反过来影响肿瘤增殖潜能与克隆组成, 抗原呈递、趋化因子、免疫代谢等相关因素参与免疫微环境异质性的时空调控[1-3]. 肝细胞癌(hepatocellular carcinoma, HCC)TIME是基于肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs)、T细胞、B细胞、NK细胞、DCs、和骨髓来源抑制细胞(myeloid-derived suppressor cells, MDSCs)等免疫细胞, 与肿瘤相互作用、相互影响形成的促肿瘤和抗肿瘤免疫特殊微环境. T细胞、NK细胞、MDSCs等免疫细胞在维持肿瘤微环境(tumor microenvironment, TME)中具有"双刃剑"作用, 既发挥免疫监视、识别和清除新生肿瘤细胞作用, 又促使肿瘤细胞发生免疫逃逸, 促进肿瘤细胞增殖和迁移[4]. 免疫细胞并不是随机分散在整个TME中, 而是以反映其生物学功能和与多种细胞(包括肿瘤细胞、基质细胞和其他免疫细胞)相互作用的模式排列[5,6]. HCC患者肿瘤局部免疫微环境异常使机体不能正常发挥免疫防御反应, 导致免疫功能低下发生肿瘤免疫逃逸、转移和复发, 通过阐明TIME不同组分在HCC复发转移中作用, 明确复杂的各种细胞、基质和分子网络相互作用, 采取针对性措施纠正HCC免疫微环境异常, 通过激活特异性有效的抗肿瘤免疫反应, 是提高HCC疗效, 降低肿瘤复发转移的关键所在.
TIME是调节肿瘤发生的外部免疫系统, 依据TIME和基因特征分为3个表型(T1-3)和2个基因簇(G1-2), T1型以高水平的调节性T细胞(T regulatory cells, Tregs)和M0巨噬细胞为特征, T2型主要与CD8+T细胞和活化的CD4+记忆T细胞相关, 而T3型特征是静止CD4+记忆T细胞、静止的DCs和活化的NK细胞. T1型特点是Tregs和M0巨噬细胞水平较高, 而M1和M2巨噬细胞在T1型水平低于T2和T3型, 不同免疫微环境下3种类型的巨噬细胞被激活并转化为具有不同分子和功能特征的亚群; T2型表现出更高水平的CD8+T细胞和活化的CD4+记忆T细胞, T3型表现出大量静息CD4+记忆T细胞、静息DCs和活化NK细胞. HCC组织中Tregs和M0巨噬细胞数量明显高于正常肝组织, CD8+T和静息CD4+记忆T细胞水平明显低于正常肝组织, T1型HCC预后不良, T2和T3型预后良好. G1基因与免疫激活和监视相关, 包括CD8+T细胞、自然杀伤细胞激活和活化的CD4+记忆T细胞, 以CD8+T细胞和活化的CD4+记忆T细胞、静息CD4+记忆T细胞、静息DC和NK细胞活化为特征, G1基因与免疫过程相关, 如T细胞受体信号通路、Th1和Th2细胞分化、免疫系统功能和补体激活; G2基因特征是M0巨噬细胞和Tregs水平升高, G2基因以高水平Tregs和M0巨噬细胞为特征, G2基因参与肿瘤发生过程, 包括P53信号通路、PI3K/Akt信号通路、细胞凋亡[7]. 依据HCC患者基因表达谱, 将免疫分为免疫激活型和免疫衰竭型, 免疫激活型显示出T细胞受体G、CD8A、IFN-γ等过度表达, 总生存率高, 免疫衰竭型以促瘤信号(如激活的间质、T细胞衰竭和免疫抑制成分)为特征, 表达受转化生长因子β1(transforming growth factor-beta 1, TGF-β1)调控的免疫抑制基因, 表达更高程序性死亡分子1(programmed death 1, PD-1)/程序性死亡配体1(programmed death ligand-1, PD-L1), 更受益于免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)治疗; 25%HCC为免疫衰竭型, 其特征为连环蛋白β1编码基因(catenin beta 1, CTNNB1)突变、T细胞缺乏和PTK2过度表达, 对ICIs治疗不应答, 50%HCC介于免疫激活型和免疫衰竭型之间, 属于免疫中间类型; 免疫衰竭型以肝脏相关的Wnt靶基因过表达、核型β-catenin染色富集和CTNNB1基因突变为特征, 其中CTNNB1途径激活与T细胞排斥相关, 此类患者表现出更低水平的免疫特征信号富集, 尤其是T细胞浸润缺乏, 影响ICIs疗效[8,9]. 基于TME肿瘤标志物分为免疫活性型、免疫缺陷型和免疫抑制型, 免疫活性型以CD45高表达和叉头框蛋白P3(forkhead box p3, Foxp3)低表达为特征, 具有相对正常的T细胞浸润, 包含抗肿瘤T细胞(CD8+CD127+T细胞、CD4+CD127+T细胞和γδT细胞)及较少浸润的B细胞(尤其是B调节细胞), 此类型HCC患者具有相对较强的抗肿瘤免疫能力, T细胞反应激活剂[如白细胞介素(interleukin 12, IL-12)和CpG寡核苷酸]和ICIs联合使用疗效和预后良好; 免疫缺陷型以CD45+低表达、CD45+细胞缺乏、DC细胞和NK细胞富集、MDSCs增加、淋巴细胞浸润减少为特征, ICIs与溶瘤病毒(如JX-594)或多肽(如LTX-315)联合应用显著增强淋巴细胞浸润, 抗肿瘤血管生成靶向药物(如索拉非尼或贝伐单抗)通过促进T细胞转运或抑制MDSCs提高ICIs对该型HCC患者疗效; 免疫抑制型以CD45、Foxp3高表达, Tregs和免疫抑制性CD4+T细胞(CD4+CD25+CD127+Foxp3+T细胞)增多, VEGFA和TGF-β1过度表达为特征, ICIs治疗可以恢复这些抑制性T细胞抗肿瘤效应, 提高免疫治疗反应效率, ICIs联合抗血管生成药物使该型HCC患者获益更多[10-12]. Teng等[13]基于肿瘤内部PD-L1表达和TILs分为4型: 适应性免疫抵抗型(PD-L1+, TIL+), 肿瘤内部存在大量TILs, 但免疫反应被PD-L1阻断, 该类型对单药ICIs治疗有效; 免疫忽视型(PD-L1-, TILs-), 肿瘤内部缺乏TILs, 无PD-L1表达, 对ICIs治疗无反应; 固有诱导型(PD-L1+, TILs-), 肿瘤有PD-L1表达, 但肿瘤内部缺乏TILs, ICIs治疗获益不大; 免疫耐受型(PD-L1-, TILs+), 肿瘤内部存在TILs, 无PD-L1表达, 肿瘤细胞通过其他免疫抑制方式逃逸, 对ICIs治疗反应差. O'Donnell等[14]基于肿瘤突变负荷(tumor mutation burden, TMB)和炎症基因特征分为4型, Ⅰ型: TMB和T细胞炎症基因高表达, 提示体内存在一种持续但功能被抑制免疫反应, 应用ICIs治疗有效, 预后较好; Ⅱ型: 低TMB且缺乏T细胞炎症基因表达, 反映抗原呈递和适应性免疫应答的启动低效或不存在, 对ICIs治疗无反应, 预后较差; Ⅲ型: TMB高于Ⅱ型但低于Ⅰ型, 缺乏T细胞炎症基因表达, 对ICIs治疗反应低下, 若通过免疫联合治疗招募T细胞或自然杀伤细胞进入肿瘤内部, 应用ICIs治疗有效; Ⅳ型: 低TMB但T细胞炎症基因高表达, 反映在免疫抑制机制中PD-1、PD-L1不占优势, 与MDSCs、Tregs和TAMs等有关, 对ICIs反应不明确. Zhang等[10]基于HCC肿瘤基因组、转录组、蛋白质组、代谢组和现象组将TIME分为免疫活性亚型、免疫缺陷亚型和免疫抑制亚型, 免疫活性亚型包含抗肿瘤T细胞(CD8+CD127+ T细胞、CD4+CD127+ T细胞和γδT细胞), T细胞浸润水平相对正常, 浸润B细胞(尤其Bregs)较少, 尿素循环通路上调, 尿素循环产生的精氨酸调节T细胞代谢, 抗肿瘤免疫力强, 预后好; 免疫缺陷亚型淋巴细胞浸润较少, 缺乏CD45+细胞(细胞减少40%), DCs和NK细胞浸润较高, CCL14能够招募单核细胞和巨噬细胞, 表现出核苷酸生物合成活性增强, 使ICIs发挥疗效空间更加局限, 预后较好; 免疫抑制亚型Tregs、Bregs、CD4+T细胞(CD4+CD25+CD127-Foxp3+T细胞)和M2型极化巨噬细胞增多, Tregs显著表达4-1BB、ICOS和Ki-67, Bregs中PD-L1和Ki-67表达增强, CD8+T细胞CTLA-4、黏液结构域蛋白3(TIM-3)和PD-1表达增加, 巨噬细胞PD-L1和IL-1β表达水平更高, VEGFA和编码肿瘤抑制性趋化因子/细胞因子(如TGF-β1、CCL-8和IL-10)基因过度表达, 糖酵解受到抑制, 线粒体呼吸作用增强, 肿瘤细胞产生更多ATP发挥免疫抑制因子作用, 预后较差. 基于免疫细胞和基质纤维成分将TIME分为免疫细胞富集纤维化(immune-enriched, fibrotic, I-E/F)型、免疫细胞富集非纤维化(immune-enriched, non-fibrotic, I-E)型、纤维化(fibrotic, F)型 和乏免疫细胞(depleted, D)型, I-E型具有高水平PD-L1表达, 有丰富TIL细胞和INF-γ, 对ICIs治疗反应良好, 若肿瘤组织有较高基因组突变负荷, 单用或与联合使用过继细胞疗法疗效好; D型实体瘤组织淋巴细胞浸润程度极低, 利用多种手段直接抑制肿瘤细胞的增殖并通过诱导细胞免疫原性死亡促进细胞内抗原释放, 增加肿瘤特异性抗原暴露而提高免疫治疗疗效, 使用治疗性肿瘤疫苗和溶瘤病毒, 将D型转变为CTLs浸润程度更高、更有利于免疫治疗I-E或I-E/F型; F型含有大量成纤维细胞和黏附分子低表达血管内皮细胞, 共同构成阻碍T淋巴细胞浸润物理屏障, 因此脆化物理屏障, 抑制成纤维细胞增殖和血管生成, 促进T细胞黏附并迁移肿瘤组织, 削弱肿瘤组织内免疫抑制因子, 活化肿瘤组织内免疫反应是治疗F型肿瘤的主要策略[15-17]. Sun等[18]依据免疫细胞组成分为3型: 免疫缺失型(D型), 由上皮细胞组成, 其他免疫细胞群维持在相对较低的水平; T细胞浸润型(T型), T细胞(包括CD4+和CD8+T细胞)浸润最高, HCC患者预后最好; B细胞浸润型(B型), 具有较高肥大细胞和cDC细胞比例; 巨噬细胞浸润型(M型), 巨噬细胞/单核细胞明显增加, 巨噬细胞分泌促进肿瘤生长、免疫抑制和细胞外基质重塑因子, 促进肿瘤进展和转移, HCC患者预后最差, B型和D型患者生存预后为中等. Xu等[19]依据免疫细胞浸润和基质富集分为免疫富集/基质贫乏1型、免疫富集/基质丰富2(immune-enrichment/matrix-poor 2, IE2)型、免疫中间/基质丰富(immune intermediate/matrix-rich, ITM)型和免疫荒漠/基质贫乏(immune desert/matrix-poor, ID)型. ITM型与Ⅲ-Ⅳ型(进展/高进展型)HCC复发密切相关, 而与Ⅰ-Ⅱ型(单发或多发性肝内寡肿瘤型)复发无关, 具有免疫治疗潜力, Ⅲ-Ⅳ型复发性HCC中, ITM型和ID型中VEGFa和PLK2表达存在显著性差异, 复发HCC免疫表型主要以IE2、ITM和ID型为特征, Ⅲ-Ⅳ型复发以ITM和ID为主, VEGFa和PLK2等分子能够逆转HCC免疫中间状态, 是潜在改善免疫环境的分子靶点. 基于TIME的不同免疫分型与HCC患者抗肿瘤能力及生存有显著相关性, 利用TIME分型能够更全面指导HCC患者免疫治疗的筛选和决策, 以提高免疫治疗疗效和评估预后, 使更多HCC患者从免疫治疗中获益.
TAMs、肿瘤中性粒细胞(tumor associated neutrophils, TANs)、Tregs、MDSCs等通过分泌IL-10、TGF-β等细胞因子抑制抗肿瘤免疫.
2.1.1 TAMs: 起源于骨髓造血微环境中的循环单核细胞、常驻巨噬细胞增殖和原位单核细胞-巨噬细胞分化及脾脏单核细胞, TAMs占HCC中免疫细胞20%-40%, 通过癌细胞重塑和生长、免疫抑制、血管生成和细胞外基质重塑促进HCC进展 [20]. 依据TAMs在TME中作用分为抑制肿瘤M1型(经典活化巨噬细胞)及促进肿瘤M2型(替代活化巨噬细胞), M1型巨噬细胞由Thl细胞因子INF-γ或脂多糖LPS诱导, 属于典型巨噬细胞, 表达高水平IL-12, 通过分泌促炎细胞因子(如IL-1、IL-6、IL-12、IFN-γ)引发炎症, 并释放活性氧(reactive oxygen species, ROS)或有毒中间体来发挥细胞毒性作用; M2型巨噬细胞释放抗炎细胞因子IL-10和TGF-β, 高表达CD206、CD163、YM1和Fizz1的M2型巨噬细胞抑制T细胞抗肿瘤免疫反应, 促进血管生成和癌细胞迁移[21-23]. 在肿瘤早期阶段, TAMs通常为M1型, 但随着TME变化, TAMs逐渐从M1型向M2型转变, M2巨噬细胞主要由Th2型细胞因子如IL-4、IL-13和M-CSF驱动产生高水平IL-10、TGF-β、生长因子和基质降解酶, 促进肿瘤增殖、血管生成和ECM重构, 导致肿瘤细胞逃逸发生转移[24,25]. 低抗原呈递能力的M2型TAMs, 被Th2细胞因子IL-4或IL-13、TGF-β或糖皮质激素极化, 分泌抗炎细胞因子, 大量表达精氨酸酶-1(arginase-1, Arg-1)、甘露糖受体和清道夫受体等, 通过阻止DCs与CTLs浸润和激活, 抑制抗肿瘤免疫, 有利于组织修复. M2型TAMs产生高水平PD-L1, 与CTLs上PD-l相互作用, 损害细胞毒性功能, 通过促血管生成促进肿瘤转移[26]. M2型TAMs通过miR-149-5p增加肝癌细胞中MMP-9表达, 降解细胞外基质, 促进肝癌细胞侵入周围组织并使其进入血液, TAMs衍生的TGF-β和EGF在肝癌细胞中诱导EMT, 增加其运动性和侵袭性, 促进肝癌细胞侵袭和转移[27,28]. TAMs诱导HCC免疫耐受机制: (1)产生TGF-β、IL-10, 诱导肿瘤周围间质单核细胞表面PD-L1表达, 抑制细胞毒性反应; (2)TAMs表面表达PD-1, 通过与PD-L1结合下调TAMs吞噬活性; (3)产生PGE2、IL-10、吲哚胺2,3双加氧酶(indoleamine 2,3-dioxygenase, IDO)诱导Tregs产生, 趋化因子CCL-17、CCL-18、CCL-22诱导Tregs聚集, 间接抑制抗肿瘤免疫; 和(4)抑制T细胞功能, 促进Tregs扩增, 招募MDSCs, 进行代谢重编程, 进行有氧糖酵解和脂肪酸氧化, 这种代谢转变维持它们促肿瘤功能, 改变TME代谢谱, 促进肝肿瘤生长、血管形成和转移能力[29-32]. 肿瘤细胞通过招募巨噬细胞并将其极化为M2型来逃避免疫监视, 将M2巨噬细胞重编程为抗肿瘤M1表型, 逆转免疫抑制微环境, 抵消TME中免疫抑制, 这种巨噬细胞重编程进一步增强CD8+T细胞浸润, 重编程M2巨噬细胞减轻CD8+T细胞活化抑制, 增强抗肿瘤免疫反应, 将M2巨噬细胞重编程为抗肿瘤M1型TAMs表型重塑TME, 是增强抗HCC肿瘤免疫的一种极具前景的治疗策略[33-35].
2.1.2 TANs: 根据TGF-β存在将TANs分为为N1(抗肿瘤)和N2(肿瘤)两种亚型, N1型TANs通过产生ROS、肿瘤坏死因子α(tumor necrosis factor alpha, TNF-α)和减少精氨酸酶表达, 通过TGF-β阻断诱导, 表达免疫活化的细胞因子和趋化因子, 增强细胞毒性并趋化肿瘤特异性T细胞而抑制肿瘤生长; N2型TANs暴露于高TGF-β水平后被诱导, 通过产生MMPs、CXCR4、VEGF及精氨酸酶, 降解细胞外基质, 表达PD-L1, 抑制CD8+T细胞免疫抑制作用, 促进肿瘤细胞增殖、迁移及血管生成[36-38]. TANs通过激活miR-301b-3p/LSAMP/CYLD通路, 增强肝癌细胞的"干性", 这些干细胞样肝癌细胞分泌趋化因子CXCL5, 招募TANs肿瘤内浸润, 构成TANs-干细胞样肝癌细胞环路, 促进肝癌细胞侵袭转移[39]. TANs通过TNF-α介导的一氧化氮生成诱导CD8+T细胞凋亡, 抑制CD8+T细胞抗肿瘤免疫, 过量产生一些趋化因子(如CCL-2和CCL-17等), 介导肿瘤内TAMs和Tregs浸润, 促进HCC进展、转移[40,41]. 中性粒细胞外诱捕网(neutrophil extracellular trap, NET)由中性粒细胞外释放去浓缩染色质、组蛋白和颗粒蛋白酶所组成的丝状结构, 通过覆盖肿瘤细胞来阻断免疫细胞的细胞毒性作用, 抑制CD8+T细胞和NK细胞增殖、活化, 调控肝癌细胞肺转移[42]. NET不仅作为"网"诱捕循环肿瘤细胞, 而且通过膜上受体与肿瘤细胞相互作用, CCDC25的C端与整合素连接激酶相互作用, 募集β-parvin, 激活β-parvin-RAC1-CDC42级联, 促进细胞骨架重排, 导致肿瘤细胞增殖和迁移[42]. TANs产生NET, 通过分泌组织蛋白酶G和MMP-9促进肿瘤生长, 导致肝癌细胞转移[43]. NET在捕获肝癌细胞后, 能诱导癌细胞抵抗死亡能力并增强侵袭能力, 继而触发其转移潜能, 通过将NET内化到捕获的肝癌细胞中, 激活TLR4/9-COX2信号通路, 增强肝癌细胞转移能力[44,45]. 富组氨酸糖蛋白(histidine-rich glycoprotein, HRG)与中性粒细胞的FCγR1相互作用, 抑制PI3K和NF-κB激活, 进而抑制IL-8诱导中性粒细胞募集和NET形成, HRG表达较低的肝癌细胞通过NET介导远处转移[46].
2.1.3 Tregs: Tregs是一类表达Foxp3、CD25、CD4为特征的T细胞亚群, 通过抑制CD8+T细胞效应器功能来抑制免疫反应, 浸润肿瘤细胞巢的Tregs数量增加, 损害CTLs增殖活化, 抑制脱颗粒、颗粒酶和穿孔素产生, 通过分泌IL-10、TGF-β1和IL-35等抑制性细胞因子, 上调CTLA-4、LAG-3和PD-1等检查点受体, 并利用颗粒酶消除效应细胞, 发挥其免疫抑制作用, Tregs通过免疫无反应和免疫抑制降低机体对肿瘤抗原识别, 诱导与免疫无反应相关肿瘤抗原的免疫耐受, 负性调节与之相关抗肿瘤免疫反应, 导致恶性肿瘤的免疫逃逸[47-50]. Tregs诱导免疫耐受机制: (1)Tregs高表达IL-2受体α链(CD25), 大量消耗IL-2, 使效应T细胞相对缺乏IL-2刺激, 抑制T细胞增殖、促进其凋亡; (2)通过非接触依赖机制如分泌抑制性细胞因子IL-10、TGF-β、IL-35来抑制效应T细胞抗肿瘤免疫应答; (3)通过共抑制分子CTLA-4表达使T细胞激活受阻; (4)通过颗粒酶B发挥细胞溶解作用, 触发免疫效应细胞凋亡; (5)通过表达CD39、CD73来促进ATP转变为腺苷, 腺苷抑制效应T细胞功能; 和(6)通过IDO抑制效应T细胞功能[51-53]. Tregs渗入TME后, 通过抑制细胞毒性CD8+T细胞和NK细胞活性, 分泌IL-10和TGF-β抑制效应细胞的增殖和功能,通过CTLA-4与免疫细胞直接相互作用, 破坏共刺激信号并诱导衰竭, 将巨噬细胞重编程为M2型TAMs, 发挥强大免疫抑制作用[54]. HBV相关HCC中CCR4+Tregs是主要Tregs亚型, 具有PD1+TCF1+干细胞样特性, CCR4+Tregs分泌IL-10和IL-35, 抑制CD8+T细胞功能. 利用中和的伪受体N-CCR4-Fc与配体CCL-22结合, 选择性地阻断肿瘤内Tregs浸润, 能够显著增强抗PD-1免疫治疗敏感性[55]. B调节细胞(B regulatory cells, Bregs)是一种具有免疫调节特性B淋巴细胞, 通过产生TGF-β、IL-10、IL-35等细胞因子发挥免疫抑制作用, Shao等[56]发现Bregs通过CD40/CD154信号通路直接与肝癌细胞相互作用, 促进肝癌细胞增殖、迁移和侵袭. 肿瘤组织中肝癌细胞释放的外泌体HMGB1使普通B细胞转化为Bregs, Bregs释放大量IL-10, 抑制CD8+T细胞功能, 介导HCC免疫逃逸[57].
2.1.4 MDSCs: 依据细胞核形态将MDSCs分为两种类型: 多形核MDSCs(PMN-MDSCs)和单核MDSCs(M-MDSCs), PMN-MDSCs通过PGE2、Arg-1和ROS介导, M-MDSCs通过免疫抑制因子(如IL-10和TGF-β)、NO和免疫调节分子(如PD-L1)介导, 抑制CTLs与NK细胞, 诱导Tregs和M2型TAMs生成, 通过VEGF、JAK等信号驱动诱导血管形成, 促进肿瘤侵袭和转移. HCC中M-MDSCs比例高, 抑制NK细胞的细胞毒性并诱导产生Tregs, 诱导HCC免疫耐受[58,59]. MDSCs损害效应T细胞及NK细胞功能机制: (1)通过表达更高精氨酸酶活性, 耗竭T细胞所需L-精氨酸、L-半胱氨酸而抑制T细胞功能; (2)产生ROS和活性氮, 下调T细胞受体链表达, 损害IL-2受体信号通路, 干扰T细胞受体和MHC相互作用, 抑制T细胞功能; (3)诱导CD4+CD25+Foxp3+Tregs扩增, 间接抑制效应T细胞功能; (4)促进肝脏巨噬细胞PD-L1表达, 抑制T细胞功能; 和(5)通过NK p30受体抑制NK细胞的细胞毒性和细胞因子释放[59-62]. MDSCs诱导免疫耐受机制: (1)通过接触性抑制方式抑制IL-2活化的NK细胞释放细胞毒素; (2)通过产生精氨酸、NO、ROS, 消化T细胞受体, 减少半胱氨酸, 干扰T细胞转运, 诱导Tregs生成和T细胞耐受抑制T细胞功能; (3)作为抗原提呈细胞, 摄取、处理并向Tregs呈递耐受抗原, 激活Tregs, 与Tregs联合抑制免疫反应; (4)通过分Arg-1、诱导型一氧化氮合酶、TGF-β、IL-10等细胞因子, 特异性抑制CD8+T淋巴细胞和NK细胞抗肿瘤功能, 诱导T淋巴细胞凋亡; 和(5)上调转录因子Foxp3在CD4+T细胞上表达, 诱导Tregs分化和扩增, 削弱效应T细胞功能, 促进肿瘤发生免疫逃逸与转移[63-66]. MDSCs促进Tregs扩增和TAM向M2表型极化, 进一步增强免疫抑制, MDSCs分泌促血管生成因子(如VEGF和bFGF), 上调血小板内皮细胞粘附分子, 促进HCC增殖、血管形成和侵袭转移[67,68]. 肝TME中的γδT细胞分泌IL-17A, 诱导肝肿瘤组织分泌CXCL5, 吸引表达CXCR2的MDSCs在肝癌组织聚集, 而且肝癌细胞可以激活β-catenin蛋白信号, 通过PF4-CXCR3轴募集MDSCs至肝脏, 促进肝癌细胞免疫逃逸和转移[69,70]. 肝癌细胞和肝星状细胞(hepatic stellate cells, HSCs)能分泌IL-6和CXCL12, 促进肝癌组织中MDSCs扩增, 激活的HSCs诱导MDSCs向肝脏迁移, 激活单核细胞内p38/MAPK信号通路促进M-MDSCs增殖及免疫抑制功能, 促进HCC进展[71,72].
T细胞衰竭是T细胞增殖和分泌细胞因子能力受损, 对刺激反应减少, 细胞因子产生受损, 增殖减少和毒性降低, 共抑制受体(如CTLA-4和PD-1)过度表达, 促进T细胞耗竭和Tregs大量积累, 循环和肿瘤内CD8+T细胞呈衰竭状态导致无法有效杀伤肿瘤[73,74]. 在CD8+T细胞中, lnc-Tim3与Tim-3竞争性结合, 导致Tim-3c端释放Bat3, 并积累催化无活性形式的Lck, 从而抑制下游T细胞信号传导(ZAP70/AP-1/NF-AT1信号传导)和内源性细胞因子(IL-2/IFN-γ)产生,释放Bat3与p300形成复合物, 增加其核易位, 增强p300依赖性p53和RelA抗凋亡基因的转录激活, 促进Tim-3+耗尽的CD8+T细胞存活, 导致CD8+T细胞耗竭[75,76]. 缺氧上调DCs和肿瘤浸润性巨噬细胞中PD-L1表达, 缺氧诱导因子1α(hypoxia-inducible factor 1α, HIF-1α)促进CD8+T细胞中免疫检查点PD-1、LAG-3和CTLA-4表达, 导致T细胞衰竭[77,78]. 肿瘤相关成纤维细胞(cancer-associated fibroblasts, CAFs)、M2型TAMs、MDSCs、Tregs、抑制性细胞因子(肿瘤细胞分泌IL-10、TGF-β等)、精氨酸酶、ROS等代谢物消耗必需氨基酸, 破坏T细胞受体信号, 诱导CD8+T细胞衰竭[79]. TAMs高表达Arg-1和IDO, 显著降低环境中色氨酸和精氨酸浓度, 导致依赖这些氨基酸激活的CD8+T细胞因代谢不足而耗竭[80]. 功能失调的T细胞表现出丰富的抑制性受体(包括PD-1、CTLA-4、LAG-3)、具有Ig和ITIM结构域的T细胞免疫受体(T cell immunoglobulin and ITIM domains, TIGIT)和T细胞免疫球蛋白和粘蛋白结构域含蛋白3等, 功能失调的T细胞不能分裂、分泌细胞因子或杀死肿瘤细胞[81]. 耗竭早期T细胞IL-2生成及杀伤能力受损, 中期TNF-α缺失, 而晚期IFN-γ和颗粒酶B产生受限[82]. CD8+T细胞是抗肿瘤适应性免疫最重要的执行者, 与正常肝脏相比, 肝肿瘤组织CD8+T细胞密度较低, 而Tregs密度较高, CD8+T细胞脂肪酸表达下调, 细胞内脂肪酸含量降低, IFN-γ分泌减少, PD-1表达上调, 导致T细胞功能衰竭[83,84]. PD-1过表达的CD8+T细胞具有免疫抑制表型, 高表达LAG3、TIGIT在内的多种耗竭相关抑制性分子, 而低表达杀伤性分子, 是HCC微环境由"活化"转为"耗竭"的重要特征[73]. HBx阳性的HCC肿瘤CD8+T细胞表达明显低于HBx阴性患者, PD-L1表达量明显高于HBx阴性患者, HBx阳性患者PD-L1水平在肿瘤细胞和一些免疫细胞(T细胞、B细胞、巨噬细胞、DCs等)中升高, HBx通过促进TME中PD-L1表达, 增强PD-1/PD-L1信号通路, 降低CD8+T细胞浸润水平, 促进HCC免疫逃逸[85]. 肝癌组织中Tregs数量与CD4+T细胞数量以及CD4+T/CD8+T比值负相关, 而与CD8+T细胞数量无明显相关性, 提示HCC组织中Tregs通过抑制CD4+T细胞增殖, 导致T淋巴细胞亚群之间平衡被破坏. 肝癌组织和癌旁肝组织TILs中CD4+T/CD8+T比值下降, 表明愈接近肿瘤部位细胞免疫受抑制愈明显, 耗竭的T细胞高表达抑制性受体, 其中PD-1是调控T细胞耗竭的主要抑制性受体; HCC癌旁肝组织中CD4+T细胞数量较癌组织明显增多, 癌旁肝组织CD4+T/CD8+T比值较癌组织升高, 提示HCC组织局部CD4+T细胞数量和CD4+T/CD8+T比值降低, 造成T淋巴细胞数量异常, 改变组织局部免疫微环境, 免疫抑制逐渐加重, 免疫监视功能减弱, 有利于肝癌细胞增殖、侵袭或转移[86]. 靶向PD-1/PD-L1和CTLA4, 改善局部缺氧环境和代谢重编程是防治T细胞功能衰竭, 增强CD8+T淋巴细胞抗HCC的重要策略.
NK细胞能够产生大量IFN-γ, 诱导穿孔素释放, 发挥细胞毒性功能并限制肿瘤细胞生长, 分泌TNF-α产生抗炎和抗肿瘤作用[87,88]. NK细胞上的NKG2D受体被肝癌细胞产生的外泌体中含有可溶性NKG2D配体(如sMICA和sMICB)结合, 阻止NK细胞识别和破坏肿瘤细胞, 损害NK监视功能, 促进HCC免疫逃逸[89,90]. HCC来源的成纤维细胞诱导NK细胞功能障碍, 活化成纤维细胞中的PGE2和IDO抑制NK细胞激活, 促进HCC肿瘤进展和转移[91]. HCC肿瘤组织内NK细胞表面CD96增加而TIGIT减少, CD96+NK细胞产生抗肿瘤相关因子(如IFN-γ、TNF-α、穿孔素及颗粒酶等)减少, 促肿瘤相关因子(IL-10、TGF-β等)增加, TGF-β使TIGIT+NK细胞向CD96+NK细胞转变, 而且TIGIT的ITIM结构直接抑制NK细胞免疫杀伤功能, 表明CD96+NK细胞在促进HCC生长和进展中发挥重要作用[92-94]. 长链非编码RNA(long non-coding rna, lncRNA)GAS5缺失通过上调miR-544抑制NK细胞中RUNX3表达, 从而抑制NCR1/NKp46信号轴, NKp46是NK细胞表面的刺激受体, 其失活会损害NK细胞杀伤活性, miR-544/RUNX3/NCR1/NKp46信号通路参与gas5介导的NK细胞毒性调控, 肝癌细胞中has-circ0007456下调可降低NK细胞对肿瘤细胞的细胞毒性, 促进肝癌细胞免疫逃逸和侵袭转移[95,96]. HCC中肝癌细胞产生TGF-β通过抑制NK细胞中IFN-γ产生和ADCC进一步削弱其抗肿瘤作用, IL-10通过抑制NK细胞增殖和细胞因子分泌(如IFN-γ和TNF-α)来削弱其杀伤活性, 降低NK细胞对肿瘤细胞杀伤作用和免疫监视功能[97-99]. 因此提高NK抗肿瘤相关因子产生, 抑制促肿瘤相关因子产生, 恢复NK杀伤肿瘤细胞功能, 是防治肝癌细胞侵袭转移的重要措施.
趋化因子(chemokines, CC)是一大类相对分子质量较小的蛋白质, 通过趋化因子受体诱导细胞迁移至靶细胞, 通过其他通路参与细胞生存、增殖、分化, 趋化因子受体(chemokines receptor, CCR)是一类跨膜G蛋白偶联受体, 其与趋化因子结合后能够激活下游信号转导通路, 从而产生不同的细胞反应. CC族趋化因子配体16主要在肝脏和肝癌细胞中表达, 可以与CCR1相互作用促进肝癌细胞肝内转移[100]. CCL2招募多种免疫抑制细胞在TME中聚集, 抑制免疫细胞的功能和活性, CCL2与肿瘤细胞表面的CCR2结合促进肿瘤生长和转移, CCL2/CCR2信号轴诱导TAMs向M2型TAMs极化, 上调细胞PDL1/L2表达, 耗尽抗肿瘤效应T细胞, 有助于肿瘤细胞发生EMT、肿瘤细胞外渗以及肿瘤定植, 促进肿瘤免疫逃逸和转移[101-103]. 趋化因子12及其受体CCR7、CCR4招募中性粒细胞参与转移前龛的形成, 促进肝癌细胞侵袭和转移, 与肝癌进程、新生血管形成、EMT及不良预后等密切相关[104,105]. CCL15通过上调PD-L1、B7-H3、IDO表达, 以自分泌方式激活STAT1/3、AKT、ERK等信号通路, 将抑制性CCR1+CD14+单核细胞募集到HCC组织中, 促进HCC肿瘤免疫逃逸和进展[106]. HCC中CCL20及其受体CCR6表达增加, 通过TCR与IL-10和TGF-β信号接触, 提高Tregs活性, 促进肝癌细胞的免疫逃逸和转移[55]. CXCR2/CXCR4轴募集MDSCs, 通过代谢产物(IL-10、IL-6分泌增多)直接抑制T细胞增殖活化, 抑制DCs而间接抑制CTLs浸润, CXCL2/CXCL4募集Tregs, 抑制效应T细胞分泌IFN-γ和IL-2, 促进肿瘤免疫逃逸, 蛋白激酶受体相互作用蛋白3(receptor-interacting protein 3, RIP3)是TNF诱导的细胞凋亡转变为坏死的核心调节因子, 肝肿瘤组织中RIP3缺乏促进CXCR2/CXCL1诱导MDSCs募集, 并减少IFN-γ+CD8+T细胞浸润, 促进HCC免疫逃逸和进展[107]. CXCR2配体募集TANs, TANs分泌TGF-β2, 触发miR-301b-3p表达, 抑制LSAMP和CYLD基因表迖, 增加肝癌细胞干细胞特性, TANs诱导肝癌干细胞样细胞通过NF-κB信号通路, 分泌更高水平CXCL5, 募集更多TANs浸润, TGF-β2/miR-301b-3p/CYLD/NF-κB/CXCL5信号通路在肝癌肿瘤干细胞样细胞和TANs间形成正反馈环作用, 导致TGF-β分泌增多, 参与HCC肿瘤进展[39].
TGF-β是一种可以调节细胞增殖、迁移、黏附的多效性细胞因子, 通过诱导DCs向调节性DCs转化而抑制机体抗肿瘤免疫, 促进TAMs向M2型分化, 促进CD4+T细胞转变为Tregs, 抑制CD8+T细胞产生INF-γ, 与IL-6、IL-10、IL-1β协同诱导Tregs生成和Thl7分化, 招募MDSCs进入TME抑制抗肿瘤反应[108-110]. HCC中TGF-β刺激DCs向调节性DCs转变, 通过上调PD-L1表达、促进效应T细胞凋亡及Tregs生成诱导免疫耐受, 促进HCC肿瘤进展[108]. TGF-β1活化微环境中HSCs, 诱导侵袭性标志物α3β1整合素表达, 下调E-Cadherin、上调E-Cadherin表达, 激活PDGF细胞内信号通路, 诱导N-Cadherin、Vimentin及CDl47表达, 促进肝癌细胞EMT发生转移[111]. TGF-β1通过调节microRNAs(如miR-23a、miR-27a、miR-24及miR-181b)上调MMP-2和MMP-9表达, 参与HCC发生、侵袭和转移[112]. TGF-β促进HCC肿瘤生长和进展机制: (1)通过抑制DCs功能和IL-2产生抑制T细胞增殖; (2)激活CAFs、肝窦内皮细胞和HSCs, 诱导Tregs产生; (3)通过激活母本抗十肽同系物(SMAD2/3)抑制因子, 与IL-21协同促进Th17细胞初始CD4+T细胞生成, 诱导IL-17表达; (4)与转录因子ATF1协同抑制CD8+T细胞IFN-γ表达, 抑制其抗肿瘤活性; (5)促进M2型巨噬细胞分化, 降低CD8+T细胞、NK细胞、DCs活性, 提高CD4+Tregs活性; 和(6)促进PD-1过度表达, 抑制T细胞增殖和细胞毒性介质(包括颗粒酶A、颗粒酶B、TNF-α和IFN-γ)产生, 导致T细胞衰竭[109,113,114]. HBV感染激活TGF-β信号抑制microRNA-34a表达, 导致CCL22产生增加, 促进CD4+CD25+Tregs募集到TIME中, TGF-β-miR-34a-CCL22信号轴的持续激活有利于肝癌细胞存活和TIME形成, 促进HCC肝内静脉转移[115]. HCC中TGF-β诱导METTL3介导的m6A修饰破坏ITIH1 mRNA稳定性, 抑制纤维连接蛋白和局灶黏附激酶信号, 驱动肿瘤生长和侵袭, TGF-β诱导m6A修饰, 破坏PCDHGA9 mRNA稳定性, 促进HCC进展和转移[116,117].
IL-10是具有广谱抗炎作用的抑制性细胞因子, 在HCC免疫微环境中, IL-10由DCs、HSCs、MDSCs等多种细胞分泌, 抑制Th1细胞生成和活化、减少细胞因子生成, IL-10诱导FcγRIIlo/-B细胞激活而抑制T细胞功能[118-120]. HCC转移患者肝脏中抗炎细胞因子IL-4、IL-5、IL-8和IL-10显著增加, 促炎细胞因子(如TNF-α、IFN-γ和IL-1)减少, 提示HCC转移患者处于抗炎状态, 促进HCC转移[121]. 与非肿瘤肝组织相比, 肝肿瘤组织中巨噬细胞和T细胞分泌IL-17, 肿瘤组织中IL-17a阳性细胞增加, IL-17a通过激活NF-κB信号通路, 上调MMP2/9表达, 促进肝癌细胞侵袭和迁移[122]. HCC肿瘤周围间质中B7-H1+单核细胞/巨噬细胞与IL-17产生细胞密度呈正相关, IL-17+巨噬细胞通过B7-H1/PD-1相互作用抑制细胞毒性T细胞功能, 肿瘤浸润Th17细胞诱导肝癌细胞产生CXCL12, 促进MDSCs向HCC微环境迁移, 肝内IL-17+T细胞、FOXP3+Tregs和肿瘤内产生IL-17细胞通过促进血管生成来促进HCC进展[123,124]. IL-33促进HCC干细胞产生, 增强肿瘤血管化、侵袭性和创造促炎TME潜力, 调节免疫微环境, 促进肝癌细胞生存、迁移、侵袭和逃避免疫监视[125]. IL-6/STAT3信号通路是炎症、免疫反应、细胞增殖和存活的关键调节因子, 通过将IL-6与其受体结合而启动, 与gp130形成复合物激活JAKs, JAKs磷酸化STAT3, 导致其二聚化、核易位和DNA结合, 该通路失调及IL-6通过OPN调控HCC干性导致HCC免疫逃逸和转移[126-128].
血管内皮生长因子(vascular endothelial growth factor, VEGF)促进肿瘤血管生成, 通过诱导DCs产生IDO, 阻止T细胞浸润肿瘤, 上调CD8+T细胞PD-1表达, 阻碍T细胞分化, 干扰CTLs功能来抑制DCs, 肿瘤源性外泌体环状RNA促进血管内皮细胞的形成, 诱导新生血管管腔的形成, 在肝癌免疫微环境中促进免疫抑制细胞浸润和免疫检查点分子表达, 促进肝癌细胞远处转移[129-132]. 血管包裹肿瘤簇(vessels encapsulating tumor clusters, VETC)是HCC中组织学特征, CD34阳性内皮细胞完全包裹肿瘤簇, VETC存在是HCC血管侵袭、复发和转移的高危因素, 以独立于EMT方式侵入血管组织结构和被包裹内皮, 在VEGF介导的转移中发挥关键作用, 为肝癌细胞提供抵抗免疫细胞攻击的保护屏障[133-135]. 因此研发针对与HCC复发转移密切相关的细胞因子分子靶向药物, 是防治HCC复发转移的重要措施.
Wnt/β-catenin信号通路被异常激活, 促进β-catenin核易位和随后基因转录, 驱动M2巨噬细胞分化, 加重免疫抑制, 促进肿瘤免疫逃避; Wnt/β-catenin信号通路不仅促进HCC肿瘤生长, 通过调节TAMs功能和表型及其对肿瘤血管生成和免疫监视影响, 而且调节免疫微环境发生免疫逃逸促进HCC进展[136,137]. β-catenin激活减少趋化因子如CCL5产生, 从而抑制CD103+DCs募集并阻止DCs抗原呈递, T细胞活化被抑制, 阻止CD8+T细胞肿瘤浸润[138,139]. Wnt/β-catenin信号通路通过c-Myc促进TAMs向M2极化, M2型TAMs中β-catenin、c-Myc和Axin2增加, 促进肝癌细胞EMT和癌细胞具有CSCs特性, 促进HCC进展[140,141]. Wnt/β-catenin信号通路作用于GSK-3β, 上调锌指转录因子(Snail)水平, 降低E-cadherin表达, 促进肝癌细胞EMT发生和肿瘤转移[142,143]. Wnt/β-catenin信号通路调节促进血管生成相关因子VEGF-A和VEGF-C表达, 有助于调节HCC血管生成、浸润和转移[144]. Yu等[145]研究发现与低侵袭性肝癌细胞相比, 高侵袭性肝癌细胞中腔隙蛋白1(caveolin-1, CAV1)表达水平更高, CAV1增强肝癌细胞侵袭性, MMP-7表达增加, 促进肿瘤生长及其向肺部转移, CAV1通过激活Wnt/β-catenin信号通路, 诱导肝癌细胞EMT, 促进HCC转移. 半乳糖凝集素-3激活β-catenin/TCF4信号通路, 调控肝癌细胞血管生成和EMT进程, 增强HCC肿瘤生长和转移[146]. YTH家族蛋白1(YTH domain family protein 1, YTHDF1)促使β-catenin入核增加, 激活TGF-β和Wnt/β-catenin信号通路下游分子TCF7、AXIN2、CCND1、MYC、PPARD表达增加, 降低HCC中CD3+和CD8+T细胞浸润, 诱导产生免疫抑制, 增强肝癌细胞肿瘤干性, 促进肝癌细胞增殖和侵袭转移[147]. 因此靶向干预Wnt/β-catenin信号通路中参与肝癌细胞侵袭转移的关键分子作用, 是防治HCC复发转移的有效措施.
LncRNAs是一类转录量超过200核苷酸且不编码蛋白质的RNA, lncRNAs在恶性肿瘤中表现出多种生物学功能, 包括表观遗传调控、DNA损伤和细胞周期调控、microRNA调控、参与信号转导、介导肿瘤细胞增殖、转移、耐药等, lncRNAs通过调节免疫细胞来影响HCC发展[148-150]. 肝癌细胞分泌的外泌体lncRNAs能协调巨噬细胞的募集、极化和活性, 巨噬细胞通过调节lncRNAs相互影响肝癌细胞行为, lncRNAs重编程TIME, 由lncRNAs介导的肿瘤细胞与微环境基质细胞间的细胞通讯对HCC发生和进展产生重要影响. LncRNAmiR4435-2HG高表达的HCC患者肿瘤中ADC、DCs、iDCs、pDCs、巨噬细胞、Tfh、Th1、Th2细胞和Tregs高浸润, T细胞共刺激、APC共刺激、CCR、免疫检查点、HLA、促炎和I类MHC富集, miR4435-2HG表达与M0、M2巨噬细胞浸润呈正相关, 与浆细胞、CD8+T细胞、Tfhs呈负相关, miR4435-2HG高表达促进HCC免疫逃逸和免疫治疗抵抗, 是HCC中TIME表征和免疫反应关键指标[151]. lncRNA BACE1-AS在肝癌细胞高表达, 通过参与EMT途径调控miR-377-3p/CELF1信号轴, 促进肝癌细胞侵袭和转移[152]. 外泌体作为HCC炎症微环境和免疫抑制微环境之间的"桥梁", 它们相互促进, 形成有利于肿瘤生长的微环境, 造血干细胞是TME重要组成部分, 通过外泌体环状RNA促进免疫逃逸, 导致HCC生长和侵袭[153]. miR-199a-3p通过干扰HSCs和循环祖细胞之间的VEGFR1、内皮细胞VEGFA及VEGF受体介导的血管生成素2之间串扰和TME基质成分, 抑制HCC转移、侵袭和血管生成[154]. 肝癌细胞外泌体miR-23a-3p、miR-155抑制T淋巴细胞免疫功能, 降低CD8+T淋巴细胞的细胞毒活性, 抑制其增殖并促进其凋亡, 抑制CD4+T淋巴细胞功能, 导致Th17/Tregs失衡促进肝癌细胞增殖和侵袭转移[155-157]. 肝癌细胞源性外泌体表面的PD-L1与CD8+T淋巴细胞表面PD-1相互作用传递抑制信号, 诱导CD8+T淋巴细胞凋亡、衰竭和失活, 抑制IL-2和IFN-γ产生, 导致T细胞耗竭, HCC发生免疫逃逸[158]. HCC分泌含有miR-146a-5p的外泌体, 被巨噬细胞摄取后激活巨噬细胞NF-κB信号通路, 诱导炎症因子产生, 促进TAMs向M2极化, 经肝癌细胞来源外泌体处理的巨噬细胞上调T细胞表面抑制受体, 包括T细胞免疫球蛋白和TIM-3、LAG-3、CTLA4、含Ig和ITIM结构域的TIGIT和PD-1表达, 下调IFN-γ和TNF-α产生, 诱导T细胞衰竭而抑制免疫, 促进肝癌细胞侵袭转移[159]. M2巨噬细胞来源的外泌体通过miR-21-5p/YOD1/YAP/β-catenin信号轴促进CD8+T细胞衰竭, Tregs来源的外泌体减少HCC中CD8+T细胞穿孔素和IFN-γ分泌, 促进HCC免疫逃逸[160,161]. circHIF1A由H/CAFs衍生的外泌体产生, 通过外泌体将circHIF1A释放到HCC细胞中, circHIF1A通过与HuR相互作用稳定PD-L1表达, 通过控制PD-L1表达, circHIF1A沉默抑制肝癌细胞增殖、运动和免疫逃逸, 提示缺氧诱导CAFs产生的外泌体circHIF1A以HuR依赖方式增加PD-L1水平, 促进肝癌细胞增殖、EMT、迁移、侵袭和免疫逃逸[162]. HCC来源的外泌体HMGB1通过HMGB1-TLR2/4-MAPK信号通路促进TIM-1+Bregs增殖, TIM-1+Bregs分泌大量IL-10和TGF-β1, 抑制CD8+T细胞扩增和效应功能, 下调细胞因子TNF-α和IFN-γ, 在HCC中形成免疫抑制微环境, 促进HCC进展[57]. HCC激活HSCs产生的外泌体circWDR25显著上调, 通过调节circWDR25/miR-4474-3p/ALOX15信号通路触发肝癌细胞EMT, 提高HSCs中CTLA-4表达和肝癌细胞中PD-L1表达, 导致免疫逃逸, 促进肝癌细胞增殖和侵袭转移[153]. 因此lncRNA和外泌体通过调控TIME中免疫细胞功能和肝癌细胞EMT, 在HCC复发转移中发挥重要生物学作用, 靶向调控与HCC侵袭、迁移密切相关的lncRNA和外泌体功能, 能够有效防治HCC复发转移.
CAFs分泌细胞外基质蛋白(如胶原蛋白), 形成物理屏障并分泌促转移因子, CAFs主要以促肿瘤细胞增殖和促进血管生成为主, 为肿瘤细胞在初期微环境中生存建立基础, 随着肿瘤进展CAFs通过分泌VEGF、FGF、PDGF促进肿瘤细胞增殖和血管生成, 通过分泌IL-6、TGF-β调节免疫细胞功能, 促进肿瘤免疫逃逸[163]. CAFs通过促进Tregs招募、抑制效应性T细胞活性及促进MDSCs积累, 导致肿瘤细胞逃避宿主免疫监视, CAFs通过促进TME酸化和低氧条件, 进一步促进肿瘤细胞侵袭和转移[164]. CAFs促进未成熟髓系细胞浸润, 该细胞整合和呈递肿瘤相关抗原至CD8+T细胞, 携带相关致死性信号PD-L2和凋亡相关配体Fas-L, 抑制肿瘤特异性CD8+T细胞浸润至TME, 导致免疫细胞浸润障碍[165]. CAFs产生的单核细胞趋化蛋白-1招募巨噬细胞至TME, 通过分泌TGF-β、IL-6促使TAMs向M2型极化, M2型TAMs产生IL-10和TGF-β增强肿瘤细胞免疫逃逸能力[166]. CAFs分泌IL-6直接作用于多种免疫细胞, 尤其是MDSCs和Tregs, IL-6通过其受体IL-6R与JAK/STAT3信号通路结合, 促进MDSCs增殖和活化, 诱导Tregs增殖和分化, 增强Tregs免疫抑制功能, 抑制效应性T细胞活性, 促进肿瘤免疫逃逸[167]. CAFs通过产生VEGF、PDGF和CXCL-12来诱导肿瘤发血管生成、侵袭转移, 通过募集免疫抑制因子和抗肿瘤免疫抑制因子促进免疫逃逸, 通过产生包括IL-1β、IL-6在内的促炎细胞因子以及CXCL12、CXCL1重塑肿瘤环境, CAFs与TME中其他免疫细胞(如T细胞、NK细胞、MDSCs、DC、TANs和TAMs)相互作用导致免疫抑制, 促进肝癌细胞增殖和侵袭转移[168,169]. 肝癌相关TAFs是HCC基质部分, 通过SDF-1α诱导外周血单核细胞迁移并分化为CD14+HLA-DR-/低MDSCs, TAFs通过IL-6/STAT3信号通路介导MDSCs生成而抑制免疫, 导致HCC免疫逃逸[168].
ECM沉积能够产生包裹肿瘤的致密纤维间质, 使得肿瘤组织较正常组织的脆性和硬度更高, 在细胞黏附和浸润中发挥重要作用, 形成阻碍免疫细胞浸润的物理屏障, 阻碍抗肿瘤药物靶向TME[170]. HCC中LOXL2、CD248、MPP2等蛋白与RAB6B共表达, 胶原修饰酶赖氨酸氧化酶样2通过修饰HCC微环境中的ECM成分来增加肿瘤组织硬度, 促进肝内转移[171]. HCC中ECM经历显著重塑, 胶原、纤维连接蛋白和HA过度沉积, 导致ECM更致密、更坚硬, 通过激活整合素介导的信号通路(如FAK和PI3K/AKT等)导致肝癌细胞增殖、侵袭转移[172]. 通过纠正HCC中TIME基质成分异常, 消除阻碍免疫细胞浸润的物理屏障, 才能更好地防治HCC复发或转移.
肿瘤血管异常增生导致肿瘤缺氧, 肿瘤细胞促进信号蛋白3A(Sema3A)分泌和巨噬细胞募集, 缺氧通过趋化因子CXCL1和CXCL2募集TANs, 缺氧诱导肿瘤细胞产生HIF-1α, HIF-1α通过上调CCL28促进TME中Tregs募集, Tregs产生TGF-β和抑制效应T细胞促进肿瘤免疫抑制微环境, HIF-1α通过TLR4/TRIF/NF-κB信号通路增强TAMs释放IL-1β, 促进肿瘤细胞免疫逃逸[173-175]. 肿瘤细胞快速增殖导致耗氧和血管生成异常加速糖酵解, 产生的乳酸是调节T细胞生物学行为重要因子, 激活缺氧诱导因子上调PD-L1表达, PD-L1与乳酸-TGFβ信号通路结合, 通过阻止CXC基序趋化因子受体3与其配体结合, 抑制辅助T细胞抗肿瘤免疫活性, 乳酸激活内皮细胞上G蛋白偶联受体81, 促进肿瘤血管生成和肿瘤细胞免疫逃逸[176-179]. HCC中肿瘤组织VEGF通过诱导Tregs、TAMs及MDSCs浸润, 诱导免疫抑制细胞因子释放, 促进肿瘤血管生成和免疫逃逸, 抑制VEGF表达能够降低TME中TAMs和Tregs, 降低TGF-β和IL-10表达, 降低T细胞衰竭标志物PD-1和TIM-3表达, 改善HCC肿瘤免疫抑制微环境[180]. 肝癌细胞增殖时缺氧诱导基因2在HCC微环境中表达增强, 刺激IL-10表达上调, 激活NK细胞中STAT3通路, 抑制NK细胞杀伤功能, 缺氧诱导HIF-1α上调, HIF-1α通过TLR4/TRIF/NF-κB信号通路促进TAMs释放IL-1β, 促进HCC复发转移[175,181]. HCC肿瘤血管异常引起缺氧破坏T细胞功能, 减少免疫刺激细胞因子, 促进免疫抑制细胞浸润, 使TAMs从CD80+巨噬细胞转化为CD206+巨噬细胞, 诱导肿瘤细胞分泌高迁移率组蛋白B1, 促使巨噬细胞向M2型极化, 释放IL-1β使环氧合酶-2上调HIF-1α和VEGF表达, 增强免疫抑制, 促进肝癌细胞侵袭转移[175,182,183]. HCC中血管异常导致肿瘤组织缺氧诱导EMT, 增强肝癌细胞中CCL20表达, CCL20通过STAT信号通路, 导致单核细胞源性巨噬细胞中IDO-1表达和活性上调, IDO-1+单核细胞诱导的巨噬细胞对抗效应T细胞, 介导对肿瘤抗原耐受性, 导致肝癌细胞转移[184]. 通过调控肿瘤血管生成, 改善肿瘤局部缺氧, 纠正TIME中免疫细胞功能异常, 是防治HCC复发转移重要研究目标.
HCC免疫微环境是一个复杂的细胞网络, 不同细胞、细胞因子、基质、信号通路等在肿瘤进展、转移、复发和治疗抵抗中具有至关重要作用, 只有全面准确了解HCC中TIME不同成分在HCC复发转移中生物学作用, 明确发挥关键作用的组分及潜在靶点, 研发针对关键细胞、基质、细胞因子和分子信号通路的药物, 才能显著改善HCC肿瘤免疫抑制微环境, 重塑正常TIME, 发挥正常抗肿瘤作用. 基于免疫分子分型指导HCC免疫治疗方案的选择, 联合分子靶向药物、手术或/和局部消融等治疗是有效提高HCC复发转移免疫治疗疗效, 改善HCC患者预后的关键.
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学科分类: 胃肠病学和肝病学
手稿来源地: 上海市
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科学编辑: 刘继红 制作编辑:张砚梁