原发性肝癌是临床面对的一个难题,目前其发病率在世界范围排名第六,死亡率在所有恶性肿瘤中排名第三[1]。肝癌是一种典型的炎症驱动的肿瘤,其往往由长期的慢性肝炎、肝硬化发展而来[2]。在危险因素如乙型肝炎病毒(hepatitis B virus,HBV)或丙型肝炎病毒(hepatitis C virus,HCV)感染、黄曲霉素B1暴露、过度饮酒、非酒精性脂肪肝的作用下,肝脏产生持续的炎症反应(包括持续的氧化应激、肝细胞坏死和再生以及纤维改变), 而这些事件都通过体细胞基因遗传变异以及表观遗传修饰的累积,导致肝癌的发生发展[3]。
对于早期肝癌,我们常常采用射频消融、手术切除、肝移植的方法[4]。而对于不能手术切除的晚期肝癌,分子靶向药物如索拉菲尼、乐伐替尼(一线)以及瑞格非尼(二线)均被证明可以显著延长患者生存期(overall survival,OS)和肿瘤进展时间(time to progress,TTP)[1]。然而,现有的肝癌治疗策略仍然不能有效控制进展期肝癌并防止其复发,这些现实情况都迫切要求我们发展新的肝癌治疗策略。
在这样的背景下,近年来,免疫治疗逐渐成为基础及临床研究的热点。肝癌能够通过多种机制诱导肿瘤免疫耐受,逃避机体免疫杀伤,最终不断进展并转移。因此,探索肝癌诱导机体免疫耐受的机制并制定针对性的免疫治疗策略,是未来肝癌治疗领域新的发展方向。本文将对肝癌诱导肿瘤免疫耐受的机制进行总结,从而为肝癌的抗肿瘤免疫治疗提供新思路。
免疫耐受机制 在肝癌免疫耐受的形成过程中,发挥主要作用的成分包括:(1)细胞成分;调节性T细胞(regulatory T cells, Tregs)、髓系衍生抑制细胞(myeloid-derived suppressor cells, MDSCs)、树突状细胞(dendritic cells, DCs)、肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs)等;(2)抑制性细胞因子;转化生长因子-β(transforming growth factor, TGF-β)、白细胞介素-10(interleukin-10, IL-10)等;(3)免疫检查点受体;程序性死亡受体-1(programmed cell death protein-1, PD-1)、细胞毒性T淋巴细胞相关蛋白-4(cytotoxic T-lymphocyte-associated protein-4, CTLA-4)、淋巴细胞活化基因-3(lymphocyte activation gene-3, LAG-3)、黏蛋白分子-3(T-cell immunoglobulin mucin-3, Tim-3)等。
调节性T细胞(Tregs) Tregs是一群以显著免疫抑制功能为特点、参与维持免疫稳态的细胞。这群细胞特征性地表达CD 25(IL-2受体α链)、CD4[5]。而后研究者又发现转录因子FoxP3的稳定表达可作为人类或小鼠Tregs更为特异的标志[6]。尽管如此,在机体发生免疫应答时除Tregs之外的一些T细胞也可以表达CD25。而Foxp3也被发现可以在一些人类效应T细胞上短暂表达。因此,用CD4、CD25和Foxp3来对人类Tregs进行分析仍存在一定不准确性。
尽管Tregs在维持机体免疫稳态方面不可或缺,但在恶性肿瘤条件下,它们可以抑制机体的抗肿瘤免疫并促进肿瘤进展[7-8]。在肝癌患者肿瘤组织以及外周血中,我们都观察到了Tregs浓度的升高,而这些Tregs也被证明能够损害CD8+T细胞的功能[9]。此外,Gao等[10]运用多因素回归分析证明,肝癌组织高浓度Tregs合并低浓度CD8+T细胞是患者生存及复发的独立影响因素。近年,随着单细胞RNA测序技术的发展,有研究指出肝癌组织浸润的Tregs的T细胞抗原受体序列(T cell receptor, TCR)序列基本不同于其他CD4+细胞,而在肝癌组织浸润的功能受损的CD8+T细胞中,约37%拥有和其他肝脏浸润CD8+T细胞同源的TCR序列[11],这也证明了肝癌组织中升高的Tregs大部分源自外周,而功能受损CD8+T细胞多半起源于肝内。这些发现均为进一步针对肝癌患者免疫治疗的研究提供了新思路。
在肝癌患者中,Tregs主要通过以下机制诱导免疫耐受的形成:(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的刺激,从而抑制增殖、促进凋亡;(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细胞的抗肿瘤免疫应答[12];(3)通过共抑制分子CTLA-4的表达使T细胞激活受阻[13];(4)通过颗粒酶B发挥细胞溶解作用,触发免疫效应细胞的凋亡[14];(5)通过表达CD39、CD73来促进腺苷三磷酸(adenosine triphosphate, ATP)转变为腺苷,而腺苷可以抑制效应T细胞的功能[15];(6)通过吲哚胺2, 3双加氧酶(indoleamine 2, 3-dioxygenase,IDO)抑制效应T细胞的功能[16]。
髓系衍生抑制细胞(MDSCs) MDSCs是从骨髓起源的、不成熟的、具有异质性的一类细胞。其几乎能在所有类型肿瘤以及感染、自身免疫性疾病、外伤等病理条件下被诱导增多。根据其表型和形态学特点,主要分为多形核(polymorphonuclear-MDSCs, PMN-MDSCs)、单核系(monocytic-MDSCs, M-MDSCs)和早期阶段MDSCs(early stage-MDSCs, eMDSCs)[17]。越来越多的研究证明,这些MDSCs不仅在表型和形态上有所区别,还有着各自独特的功能和生化特点,在不同病理条件下扮演不同的角色。但是,现有的亚类之间仍存在部分重叠,因此研究者仍需对MDSCs进行更为细致的分析,才能对其更好地进行鉴定。
在健康肝脏,衰老肝细胞通过CCR2(C-C motif chemokine receptor 2)-CCL2(C-C motif chemokine receptor 2)信号招募MDSCs[18],而这些MDSCs可以分化为巨噬细胞并阻碍肝癌发生。但在肝癌进展时,MDSCs失去分化能力并通过多种机制损害机体抗肿瘤免疫,其被多个研究证明是肝癌患者预后以及术后复发的重要影响因素[19-20]。
在肝癌患者,MDSCs已被证明可以通过如下机制损害效应T细胞以及自然杀伤细胞(natural killer cell, NK)的功能:(1)通过表达更高的精氨酸酶活性,耗竭T细胞功能所需L-精氨酸、L-半胱氨酸来抑制T细胞功能[21];(2)产生活性氧(reactive oxygen species, ROS)和活性氮(reactive oxygen species, RNS)。这些活性成分通过下调T细胞TCR链的表达、损害IL-2受体信号通路、干扰TCR和主要组织相容性复合体(major histocompatibility complex, MHC)的相互作用从而抑制T细胞功能[22];(3)诱导CD4+CD25+Foxp3+Tregs扩增,间接抑制效应T细胞的功能[23];(4)促进肝巨噬细胞程序性死亡受体-配体1(programmed cell death-ligand 1, PD-L1)表达,抑制T细胞功能[24];(5)通过NK p30受体来抑制NK细胞的细胞毒性和细胞因子的释放[25]。
树突状细胞(DCs) DCs是专业抗原呈递细胞(antigen presenting cells, APCs)的一种,几乎在所有组织中存在。由于其能够同时调控免疫应答及免疫耐受,故在调节免疫方面扮演着非常重要的角色[26]。DCs是一个具有异质性的群体,主要组成为:(1)浆细胞样树突状细胞(plasmacytoid dendritic cells, pDCs), 具有分泌大量1型干扰素的功能,因此经常活跃在抗病毒免疫的第一线[27];(2)经典树突状细胞(classical dendritic cells, cDCs),又可分为cDC1、cDC2[28],由不同的骨髓祖细胞分化而来[29],它们能够特异性激活细胞毒性反应以及辅助性T细胞17(T helper cell 17, Th17)或Th2应答[30-31];(3)在肿瘤背景下,往往还存在另一种亚群单核细胞衍生树突状细胞(monocyte-derived DCs, Mo-DCs)[32],这些细胞和TAMs紧密相关,并往往具有致免疫耐受的能力[33]。一篇涉及18 000多位肿瘤患者、39种不同类型肿瘤的meta分析证明肿瘤的预后不仅取决于DCs的成熟和激活状态,还与其亚群组成有关[34]。
在肝癌患者,我们通常将这部分在肝癌免疫微环境中发挥免疫抑制作用的DCs亚群称为调节性DCs。调节性DCs不是指特定的细胞群体,而是具有异质性的具有免疫抑制功能的DCs的总称。有报道称,在肝癌早期到进展期的过程中,DCs往往会从免疫激活的状态转变为免疫抑制的状态[35]。
调节性DCs诱导肝癌免疫耐受的机制包括:(1)肿瘤抗原呈递能力降低以及不成熟的DCs表型如低表达的共刺激分子和MHC分子[36];(2)通过分泌IL-10诱导FcγRIIlo/- B细胞激活从而抑制T细胞功能[37],此外也能促进CD4+T细胞分泌IL-10[38];(3)Song等[39]证明TGF-β可以刺激DCs向调节性DCs转变,并通过上调PD-L1表达、促进效应T细胞凋亡以及Tregs生成来诱导肝癌免疫耐受形成;(4)表达免疫检查点分子如PD-L1、PD-L2,通过与T细胞表面PD-1结合传递抑制信号,在小鼠模型上研究者证明通过阻断DCs表面PD-L1可以提高DCs触发T细胞免疫应答的能力[40];(5)通过色氨酸代谢酶IDO1/IDO2耗效应T细胞所需氨基酸,从而抑制效应T细胞功能[41]。
肿瘤相关巨噬细胞 我们通常把在肿瘤区域浸润的巨噬细胞称为TAMs。现已证明,TAMs能够促进肿瘤细胞增殖、血管生成、侵袭及转移,在肿瘤的发生发展中扮演着重要的角色[42]。根据巨噬细胞平衡理论,TAMs拥有两种不同的表型:经典激活的巨噬细胞(M1)是由Th1分泌细胞因子干扰素-γ(interferon-γ, INF-γ)或脂多糖(lipopolysaccharides,LPSs)等微生物抗原激活的,它们通过释放氧自由基或毒性介质发挥经典的细胞毒性作用;而选择性激活的巨噬细胞(M2)抗原呈递能力很低,通常由Th2分泌的细胞因子IL-4、IL-13、TGF-β或糖皮质激素诱导产生,可以减轻炎症从而促进组织修复[43]。
在肝癌患者,肝癌细胞可以通过分泌血管内皮生长因子(vascular endothelial growth factor, VEGF)、血小板衍生生长因子(platelet-derived growth factor,PDGF)、TGF-β、CCL-2、巨噬细胞集落刺激因子(macrophage colony stimulating factor, M-CSF)募集并激活TAMs[43]。此外,肝癌细胞表面磷脂酰肌醇聚糖-3的表达也被证明参与了对TAMs的招募[44]。越来越多的研究证据表明,肝癌组织TAMs通常表现为M2表型并和患者不良预后[45]以及肿瘤侵袭性[46]相关。
TAMs诱导肝癌免疫耐受的机制包括:(1)产生TGF-β、IL-10,并诱导肿瘤周围间质单核细胞表面PD-L1的表达,从而抑制细胞毒性反应[47];(2)Gordon等[48]发现TAMs表面也表达PD-1,通过与PD-L1结合可以下调TAMs吞噬活性,但该机制是否在肝癌中同样扮演重要角色还需进一步的研究;(3)TAMs产生的前列腺素E2(prostaglandin E2, PGE2)、IL-10、IDO可以诱导Tregs产生[49],而趋化因子CCL17、CCL18、CCL22可以诱导Tregs的聚集[43],从而间接抑制抗肿瘤免疫。
其他细胞成分 肿瘤相关成纤维细胞(cancer-associated fibroblasts,CAFs)、肝星形细胞(hepatic stellate cells,HSCs)和内皮细胞(endothelial cells, ECs)也参与了肝癌免疫耐受微环境的形成。其中HCC相关CAFs(1)通过释放PGE2、IDO来诱导NK细胞功能紊乱[50];(2)通过IL-6-STAT3通路来促进调节性DCs的产生[41];(3)通过分泌IL-6、基质细胞衍生因子-1(stromal cell derived factor-1, SDF-1)诱导MDSCs产生并激活[51];(4)诱导肿瘤浸润中性粒细胞表面PD-L1表达[52]。研究者在小鼠原位肝癌模型上证明HSCs可以通过激活COX2-PGE2-EP4信号通路,诱导Tregs和MDSCs产生,从而实现免疫抑制[53-54]。此外,HSCs和ECs也可以产生SDF-1并诱导骨髓细胞在肿瘤区域的聚集[55],而激活的内皮细胞也可通过TGF-β来介导Tregs的产生。
抑制性因子 在肝癌免疫微环境中,肿瘤细胞及多种免疫细胞可通过分泌免疫抑制因子来诱导免疫耐受的形成,其中以TGF-β、IL-10、VEGF等较具代表性。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[56],其可通过多种途径抑制机体抗肿瘤免疫,包括诱导DCs向调节性DCs转化[39]、促进肿瘤相关巨噬细胞向M2型分化、促进CD4+T细胞转变为Tregs,并抑制CD8+T细胞和NK细胞的功能[56];IL-10是具有广谱抗炎作用的抑制性细胞因子[57]。在肝癌免疫微环境中,IL-10可由DCs、HSCs、MDSCs等多种细胞分泌[57]。研究表明,IL-10既可作用于APCs,抑制其呈递抗原及表达MHCII分子、共刺激分子CD80/CD86,也可直接抑制T细胞功能以及促炎细胞因子IL-1、IL-6、IL-12、肿瘤坏死因子(tumor necrosis factor, TNF)的释放[58];传统观点认为,VEGF在肿瘤组织中主要发挥促进血管生成的作用,但如今其被报道可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的表达[58]。
此外,肝癌细胞或免疫细胞还可以产生一系列可溶性因子来调节免疫。IDO是色氨酸代谢的关键酶,IDO表达的升高可以通过耗竭T细胞功能所需的色氨酸来抑制效应T细胞功能,且其代谢产生的犬尿氨酸也可诱导Tregs生成[59]。在肝癌患者,IDO在DCs、TAMs、CAFs、ECs、肝细胞的表达均可升高[50, 60],而其也被证明与肝癌侵袭性以及患者不良预后相关[61]。此外,在肝癌免疫微环境中,精氨酸酶-1主要在MDSCs和M2型TAMs表达升高,其主要通过耗竭T细胞功能所需L-精氨酸来维持免疫耐受[62-63];腺苷也可作为免疫调节因子,来自腺苷受体A2a的信号可以抑制巨噬细胞激活、CD4+和CD8+T细胞功能以及诱导Tregs产生[15, 64]。
免疫检查点 研究表明,即使在肿瘤组织存在足量的肿瘤相关抗原(tumor-associated antigen,TAA)-特异细胞毒性T细胞,肿瘤往往仍会进展。这是因为人体可以通过多种机制损害细胞毒性T细胞的功能[65]。其中最显著的途径就是免疫检查点途径,包括PD-1-PD-L1/PD-L2、CTLA-4、Tim-3、LAG-3、淋巴细胞衰减子(B and T lymphocyte attenuator, BTLA)[66]。目前研究最多的、临床相关性最大的是PD-1/PD-L1、CTLA-4。
PD-1在一系列免疫细胞上均可表达,包括活化的T细胞、B细胞、NK细胞以及Tregs、MDSCs、DCs、TAMs[48, 67]。PD-1传递的信号可以诱导CD8+/CD4+T细胞的凋亡、抑制Tregs的凋亡、以及损害DCs和TAMs的功能。PD-1有PD-L1和PD-L2两个配体。PD-L1在造血细胞、内皮细胞、上皮细胞表面均有表达,而PD-L2只在造血细胞表面表达。在肝癌免疫微环境中,PD-L1主要表达在kupffer细胞表面,此外还有APCs、肿瘤细胞表面[68]。当高表达PD-L1的细胞与高表达PD-1的CD8+T细胞相互作用,可引起效应T细胞的功能障碍。目前,PD-1抗体纳武单抗已在临床Ⅰ/Ⅱ期试验中被证明对进展期肝癌有效,并具有良好的安全性[69],已被美国食品药品监督管理局(Food and Drug Administration,FDA)批准作为进展期或转移性肝癌的二线治疗药物[70]。而PD-1另一抗体派姆单抗的疗效也已在临床Ⅱ期试验中得到验证[71],并被FDA批准用于经索拉菲尼治疗的肝癌患者[70]。此外,PD-L1抗体得瓦鲁单抗也已进入临床Ⅰ/Ⅱ期试验[72]。
CTLA-4是CD28的同系物,它可以通过直接传递抑制信号或与CD28竞争性结合APCs表面的CD80/CD86来抑制T细胞功能[73]。CTLA-4不仅在活化T细胞上表达,也在Tregs表面表达,并在Tregs发挥免疫抑制功能的过程中扮演重要的角色。如HCC衍生Tregs可以通过CTLA-4下调脾脏DCs上CD80/CD86的表达[74]。有研究者通过对31例肝癌患者的研究发现抗CTLA-4抗体可以使TAA-特异细胞毒性T细胞的数量增加60%,并提高其抗肿瘤能力[75]。CTLA-4抗体依匹单抗、曲美替尼对于进展期肝癌的疗效目前也已进入临床Ⅰ/Ⅱ期试验[72]。
Tim-3作为一种新发现的免疫检查点分子,已在实验室中被证明可作为多种肿瘤的治疗靶点,其在多种免疫细胞表面如CD4+/CD8+T细胞、Tregs上均有表达,并可作为多种配体包括半凝乳素-9(galetin-9, Gal-9)、磷脂酰丝氨酸(phosphatidylserine, PtdSer)、高迁移率族蛋白B1(high mobility group box-1 protein, HMGB1)、癌胚抗原相关的细胞黏附分子-1(carcinoembryonic antigen-related cell adhesion molecule-1, CEACAM-1)的受体,其中Gal-9主要在APCs表面表达。研究者发现在HBV相关HCC,Tim-3/Gal-9信号通路可以介导T细胞的老化[76]。此外,TGF-β可以上调TAMs表面Tim-3表达并促使TAMs分泌IL-6以及向M2转化[77]。
LAG-3被证明在肝癌浸润淋巴细胞上表达,尤其是CD8+T细胞[40]。LAG-3和Gal-3的相互作用可以抑制CD8+T细胞以及NK细胞的功能,其表达与肝癌患者预后具有明显的相关性[78-79]。
BTLA也是一种表达在活化淋巴细胞表面的共抑制分子,它的配体是可表达在肝癌细胞表面的单纯疱疹病毒进入介质(herpesvirus entry mediator,HVEM),因此肿瘤细胞表面具有HVEM表达的肝癌患者肿瘤侵袭性更强且预后更差[80]。
结语 近年来,免疫治疗在肝癌的系统治疗中扮演着越来越重要的角色,关于肝癌免疫治疗的基础及临床研究进展也在不断更新。然而,以PD-1或PD-L1、CTLA-4抗体为代表的免疫治疗疾病缓解率低,其最主要的原因是肝癌免疫耐受微环境的形成机制错综复杂,单药免疫治疗难以获得较高临床缓解率。Tregs、MDSCs,TAMs、调节性DCs等多种免疫细胞及其分泌的免疫抑制因子共同诱导了肝癌免疫耐受微环境。这提示我们在制定抗肿瘤免疫治疗策略时,必须结合多个免疫治疗靶点或其他肝癌治疗策略如化疗、靶向治疗,从而进一步改善晚期肝癌患者的生存质量。
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