肿瘤相关巨噬细胞的极化及其对肿瘤治疗的影响

doi:10.3969/j.issn.1000⁃484X.2019.08.026肿瘤相关巨噬细胞的极化及其对肿瘤治疗的影响①张子明　柴国静②　宋淑霞(河北医科大学免疫教研室,河北省重大疾病免疫机制及干预实验室,石家庄050017) 中图分类号　R392 文献标志码　A 文章编号　1000⁃484X (2019)08⁃1018⁃08①本文为国家自然科学基金(81071710)㊁河北省自然科学基金(H2014206180)和河北省高等学校科学技术研究重点项目(ZD2017049)资助项目㊂②河北省人民医院检验科,石家庄050000㊂作者简介:张子明,男,硕士,主要从事肿瘤外泌体介导肿瘤耐药机制研究,E⁃mail:403546919@㊂通讯作者及指导教师:宋淑霞,女,博士,教授,硕士生导师,主要从事肿瘤免疫微环境研究,E⁃mail:songsxmy @㊂[摘　要]　可塑性和多样性是巨噬细胞的重要特征,根据其功能不同,巨噬细胞被分为经典活化型即M1型,替代活化型即M2型㊂诱导M1和M2型巨噬细胞分化的条件不同,M1和M2型巨噬细胞的表型及功能也存在差异㊂在多数肿瘤微环境中存在M2型的巨噬细胞,该细胞通过产生多种细胞因子及蛋白酶参与肿瘤血管形成,并促进肿瘤的增殖及转移㊂因此,靶向抑制M2型巨噬细胞分化㊁清除M2型巨噬细胞等措施已成为肿瘤治疗研究的重要领域㊂本文主要对巨噬细胞的极化㊁肿瘤微环境对肿瘤相关巨噬细胞极化的影响及靶向肿瘤相关巨噬细胞的治疗策略进行综述㊂[关键词]　肿瘤相关巨噬细胞;M1极化;M2极化;靶向治疗Polarization of tumor⁃related macrophages and its potential role in tumor therapyZHANG Zi⁃Ming ,CHAI Guo⁃Jing ,SONG Shu⁃Xia .Department of Immunology ,Hebei Medical University ,Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province ,Shijiazuhang 050017,China[Abstract ]　Plasticity and diversity are important characteristics of macrophages.According to their different functions,macrophages are classified into the classic activated type,M1type,and the alternative activated type,M2type.Not only the inducers for M1and M2macrophages differentiation were different,but the phenotypes and functions of M1and M2macrophages were different.M2macrophages exist in most of the tumor microenvironment.Furthermore,the M2type macrophages could secret many cytokines,chemokines and protease which involved in tumor angiogenesis,and promote the gowth and metastasis of tumor.Therefore,targeted inhibition of differentiation of M2⁃type macrophages and elimination of M2⁃type macrophages have become an important research area intumor treatment.[Key words ]　Tumor associated macrophage;M1differentiation;M2differentiation;Target therapy 巨噬细胞是肿瘤微环境中重要的基质细胞,约占肿瘤总重量的一半,被称为肿瘤相关巨噬细胞(Tumor⁃associated macrophages,TAM )[1]㊂TAM 是一个不均一的群体,既有促肿瘤作用的M2型巨噬细胞,也有抑制肿瘤的M1型巨噬细胞㊂由于肿瘤微环境存在有利于M2型巨噬细胞分化因素,多数肿瘤的微环境中存在M2型巨噬细胞,对肿瘤的生长㊁侵袭㊁转移起着关键作用㊂因此,研究肿瘤微环境中诱导TAM 极化的因素㊁TAM 对肿瘤治疗的影响,对提高肿瘤疗效意义重大㊂1　肿瘤相关巨噬细胞的极化多种组织或器官都有单核巨噬细胞分布,如肠㊁肝脏㊁肺㊁皮肤㊁腹膜和心脏,不同组织定居的巨噬细胞表型各异㊁功能也不同,因此,可塑性和多样性是单核巨噬细胞的重要特征[2]㊂研究表明,不同组织的巨噬细胞受微环境中不同信号的诱导,发挥不同的功能,如微生物㊁组织损伤㊁细胞因子及微生物代谢产物均可活化单核巨噬细胞㊂仿照Th1/Th2细胞的分类方法,将被不同激活物激活㊁发挥不同功能的单核巨噬细胞也分为M1和M2两个极化的群体㊂M1和M2产生细胞因子的能力不同,M1产生高水平的IL⁃12㊁CXCL9和CXCL10,低水平的IL⁃10㊁CCL17和CCL22;而M2细胞产生的IL⁃10㊁CCL17和CCL22水平较高㊂1.1　M1型巨噬细胞的极化与激活　M1型巨噬细胞是一种对微生物和肿瘤细胞具有杀伤活性的效应细胞㊂它典型的特征为高抗原呈递㊁高产IL⁃12㊁IL⁃23及NO,高表达MHC Ⅰ类和MHC Ⅱ类分子[3]㊂M1细胞通过产生促炎细胞因子㊁活性氧㊁氧化物和蛋白酶在微生物的杀灭和组织重建中起重要作用,其激活的主要方式是通过LPS㊁IFN⁃γ及GM⁃CSF 三种信号㊂1.1.1　LPS 诱导信号㊂LPS 可被巨噬细胞TLR4所识别,两者结合将信号转导到胞内,并由两个衔接蛋白髓样分化因子88(Myeloid differentiation factor 88,MYD88)和TRIF 相关接头分子(TRIF⁃related adaptor molecule,TRAM)介导下游信号㊂MyD88信号途径介导一系列激酶IRAK4㊁TRAF6和IKKβ的激活,最终激活NF⁃κB㊂NF⁃κB 是调节一系列炎性基因的关键转录因子㊂TRAM 衔接蛋白通路激活转录因子IRF3从而诱导Ⅰ型干扰素(如:IFNα和IFNβ)的表达和分泌㊂Ⅰ型干扰素与Ⅰ型干扰素受体IFNAR 结合,激活转录因子STAT1[4⁃6]㊂因此LPS 介导的M1型巨噬细胞的活化主要受NF⁃κB㊁AP⁃1㊁IRF㊁STST1调控并改变基因的表达㊂1.1.2　IFN⁃γ诱导信号㊂当IFN⁃γ与IFNGR 结合后,募集Jak1和Jak2接头蛋白,活化转录因子IRF1和IRF8,诱导多种细胞因子受体,如IL⁃6R㊁IL⁃12RA 和IL⁃15R 的表达,同时促进黏附分子ICAM1㊁整合素α的表达㊂另外,IFN⁃γ还可以通过影响巨噬细胞的糖代谢途径进而促进M1的分化,如IFN⁃γ可以促进线粒体产生活性氧(Reactive oxygen species,ROS),诱导低氧诱导因子⁃1α(Hypoxia inducible factor⁃1α,HIF⁃1α)高表达,并随之产生IL⁃1β等炎症因子[7]㊂图1　经典活化型巨噬细胞(M1型巨噬细胞)Fig.1　Classical activated macrophages (M1macropha⁃ges )Note:LPS,IFN⁃γand GM⁃CF induced differentiation of M1⁃typemacrophages by activating STAT1,NF⁃κB,AP⁃1and IRFs.1.1.3　GM⁃CSF 诱导信号㊂GM⁃CSF 是一种造血生长因子,来源于T 细胞㊁巨噬细胞㊁内皮细胞和成纤维细胞等[8]㊂GM⁃CSF 与其受体结合后,从而招募JAK2并激活STAT5㊁ERK㊁NF⁃κB 及IRF5,产生一系列促炎细胞因子㊂GM⁃CSF 与LPS 相比,LPS 诱导的巨噬细胞可分泌更高水平的促炎细胞因子[9]㊂M1型巨噬细胞极化见图1㊂1.2　M2型巨噬细胞的极化与激活(图2)　M2型巨噬细胞的特征是高表达Arg⁃1㊁YM1㊁Mrx1㊁Dectin⁃1㊁DC⁃SIGN㊁甘露糖受体㊁清道夫受体A㊁清道夫受体B⁃1㊁CD163㊁CCR2㊁CXCR1㊁CXCR2,同时低表达促炎症细胞因子,参与组织重塑[10]㊂根据刺激物的不同,M2型巨噬细胞可以进一步划分为M2a㊁M2b㊁M2c 及M2d 四个亚型,它们典型的特征是产生Arg⁃1酶,高表达IL⁃10和IL⁃1RA,低表达IL⁃12[11,12]㊂M2a 型TAM 主要产生趋化因子CCL24㊁CCL22,分别与CCR3和CCR4结合促进嗜酸性粒细胞㊁嗜碱性粒细胞及Th2细胞募集,介导Th2型免疫应答,并由Th2细胞㊁嗜酸性粒细胞和巨噬细胞产生的IL⁃4或IL⁃13所诱导㊂IL⁃4或IL⁃13与其受体IL⁃4Rα或IL⁃13Rα结合引发JAK1和JAK3的募集,进一步激活STAT6和IRF4㊂M2b 型巨噬细胞可分泌CCL1,与CCR1结合后促进嗜酸性粒细胞㊁Th2及Treg 细胞的募集,参与体液免疫和免疫调节作用㊂M2b由图2　替代活化型巨噬细胞(M2型巨噬细胞)Fig.2　Alternative activated macrophages (M2macropha⁃ges )Note:IL⁃4and IL⁃13can induce M2a macrophages differentiation bySTAT6/IRF4signals.Differentiation of M2b can be induced by IL⁃1R or immune complexes by Syc and PI3K activation.M2c dif⁃ferentiation can be induced by glucocorticoid or IL⁃10viaactivation of STAT,NK⁃κB and MKP⁃1.M2d differentiation is depended on cAMP production by activation of Adenosine receptor A2A via NF⁃κB signal.IL⁃1R或免疫复合物联合LPS所诱导,信号传递涉及细胞内的脾酪氨酸激酶(Spleen tyrosine kinase, Syc)和磷酸肌醇3⁃激酶(Phosphoinositide3⁃kinase, PI3K),进而激活丙氨酸氨基转移酶(Alanine amin⁃otransferase,ALT)和细胞外调节蛋白激酶(Txtracellular regulated protein kinases,ERK),从而诱导IL⁃10和TNF⁃α高表达[11,13]㊂M2c型巨噬细胞可由糖皮质激素(Glucocorticoids,GC)㊁TGF⁃β和IL⁃10所诱导,主要通过产生CXCL13㊁CCL16和CCL18促进初始T细胞㊁嗜酸性粒细胞的募集,介导免疫抑制[11]㊂糖皮质激素扩散到细胞内与其受体相结合形成复合物,进而转移到细胞核内,并抑制NF⁃κB 和AP⁃1的活性,从而干扰炎症反应[14]㊂IL⁃16和腺苷是诱导M2d分化的重要刺激物㊂腺苷协同TLR4 (TLR2/7/9)的激动剂是将M2a向M2d分化的开关㊂腺苷信号抑制TLR依赖的TNF⁃α㊁IL⁃12等炎症因子产生,并促进IL⁃10㊁VEGF的产生[15]㊂M1和M2型巨噬细胞的区别见表1㊂2　肿瘤微环境对M2型巨噬细胞的影响1863年Virchow描述了肿瘤组织中炎性白细胞的存在,第一次将炎症与癌症联系起来,并提出 淋巴网状浸润”是慢性炎症引发肿瘤发生的原因[16]㊂TAMs是实体瘤基质的主要成分,是具有高可塑性的异质细胞,既有经典的M1型巨噬细胞,也有M2型巨噬细胞,因此,在肿瘤微环境中,巨噬细胞是一把双刃剑㊂由于肿瘤微环境会抑制免疫功能,TAM一般被极化为M2型巨噬细胞并发挥促瘤作用[17],但在不同肿瘤组织中,M2型巨噬细胞极化的机制不同㊂Quail等[18]研究表明,胶质瘤组织中有大量CD3+T 及CD3+CD8+T细胞的浸润,并分泌高水平的IL⁃4㊂IL⁃4通过活化NFAT和Stat6两个转录因子,诱导M2型TAM分化,并促进TAM分泌IGF⁃1,进而发挥促进胶质瘤生长的作用㊂乳酸是实体肿瘤的代谢产物,乳酸通过激活TAM的ERK/STAT3信号分子,诱导M2型TAM分化,并促进乳腺癌的生长和转移[19]㊂肿瘤相关成纤维细胞(Cancer⁃associated fbroblasts,CAFs)是肿瘤微环境中重要的基质细胞, CAFs产生的TGF⁃β和α⁃SMA促进肿瘤细胞发生EMT及转移;CAFs释放的SDF⁃1/CXCL12㊁CCL2促进内皮细胞前体向肿瘤组织募集及血管生成㊂另外,在前列腺肿瘤中,CAFs产生的SDF⁃1/CXCL12也是诱导M2型TAM极化的诱导因子[20]㊂有文献报道,顺铂或卡铂处理人宫颈癌细胞株HELA㊁CC8㊁CSCC7或人卵巢癌细胞株COV413B和CAOV3后的培养上清可诱导人外周血CD14+单核巨噬细胞分化为M2型巨噬细胞[21];Challagundla等[22]报道,成神经细胞瘤(Neuroblastoma,NBL)释放的外泌体富含miR⁃21,将此外泌体与单核细胞共培养后,将此单核细胞注射给荷瘤小鼠,可明显增加荷瘤小鼠对顺铂的抗性㊂因此,肿瘤微环境存在多种诱导M2型TAM分化的机制㊂3　肿瘤相关巨噬细胞与肿瘤治疗3.1　抑制巨噬细胞的募集　由于肿瘤微环境中存在多种诱导M2型巨噬细胞极化的因素,抑制巨噬细胞的募集可能有利于肿瘤的治疗㊂抑制巨噬细胞的募集主要是通过防止肿瘤及肿瘤间质细胞分泌趋化因子和阻断巨噬细胞的表面受体㊂在巨噬细胞募表1　M1和M2型巨噬细胞的特征及功能的差异Tab.1　Differences in characteristics and functions of M1and M2macrophagesType of macrophage M1M2a M2b M2c M2dPolarization inducer IFN⁃γ,LPS,TNF⁃αIL⁃4,IL⁃13Immune complex,TLRagonists,IL⁃1βGlucocorticoid,IL⁃10,TGF⁃βTLR agonists,Adenosinereceptor ligandCharacteristic mole⁃cules CD80,CD86,CD68,MHCⅡ,IL⁃1R,TLR⁃2,TLR⁃4,iNOS,IL⁃10low,IL⁃12highMMR/CD206,IL1Ra;IL⁃1RII,Arg⁃1,FIZZ1,Ym1/2IL⁃10high,IL⁃12low,CD86MMR/CD206,TLR⁃1,TLR⁃8Arg⁃1VEGF,IL⁃12low,TNF⁃αlow,IL⁃10highCytokines TNF⁃α,IL⁃1β,IL⁃6,IL⁃12,IL⁃23,IL⁃27,CXCL9,CXCL10,CXCL11,CXCL16,CCL5,iNOS,ROSIL⁃10,TGF⁃β,CCL17,CCL18,CCL22,CCL24TNF⁃α,IL⁃1β,IL⁃6,IL⁃10,CCL1IL⁃10,TGF⁃β,CCL16,CCL18,CXCL13IL⁃10,VEGFFunctions Promote inflammation,induceTh1response,anti⁃tumor Anti⁃inflammation andissue repairInduce Th2response,immune regulationPhagocytosis ofapoptotic cellsAngiogenes and tumorpromotion集中起主要作用的是单核细胞趋化蛋白⁃1 (Monocyte chemotactic protein1,MCP⁃1)即CCL2,其表达水平和巨噬细胞的募集密切相关㊂据报道, CCL2存在于许多类型的肿瘤微环境中㊂小分子抑制剂Bindarit可有效减少CCL2阳性黑色素瘤中CCL2的释放和巨噬细胞的募集[23]㊂在Ⅰ期临床试验中,抗CCL2抗体carlumab(CNTO888)在晚期实体瘤患者中显示出初步的抗肿瘤活性,并且耐受性良好[24]㊂CCR2抑制剂PF⁃04136309(是一种口服的小分子CCR2抑制剂,可防止炎性单核细胞从骨髓中渗出,减少TAMs的浸润)联合FOLFIRINOX (为标准化疗方案由奥沙利铂㊁依立替康㊁亚叶酸钙㊁和氟尿嘧啶构成)的CCR2靶向治疗对局部晚期胰腺癌和临界可切除胰腺癌是安全有效的[25]㊂CCR2抑制剂可以降低TAMs,改善肿瘤微环境,因此可以为今后癌症治疗的临床研究提供重要依据㊂在前列腺癌中,CCL2可上调其受体表达,并通过CCL2⁃CCR2信号上调CCL22和CCR4的表达,进而CCL22⁃CCR4轴激活Akt,导致前列腺癌迁移和侵袭[26]㊂CCR4比CCR2的促肿瘤迁移和侵袭的能力更强㊂因此靶向CCL22⁃CCR4轴可能成为治疗前列腺癌的潜在靶点[26]㊂在结直肠癌肝转移患者中, CD4+和CD8+T淋巴细胞产生高水平的CCL5,并具有明显的促瘤作用㊂因此靶向抑制CCR5可能成为治疗肿瘤的一种选择㊂Maraviroc是一种高度选择性的,良好耐受的CCR5抑制剂,经过MARACON试验证实,在术后转移性结直肠癌患者中,对maraviroc治疗没有显著的副作用㊂因此,靶向CCL5⁃CCR5轴的治疗方法值得进一步研究[27]㊂此外,其他的趋化因子(CCL3㊁CCL4㊁CCL5㊁CXCL8㊁CXCL12)㊁集落刺激因子⁃1(Colony stimulating factor⁃1,CSF⁃1)㊁内皮性单核细胞活化多肽2(Endothelial monocyte activation polypeptide2, EMAP2)和生长因子(VEGF)㊁内皮素2㊁血小板源性生长因子(Platelet derived growth factor,PDGF)等也参与巨噬细胞的募集㊂所以,可使用针对这些因子的抑制剂进行研究来判定靶向的有效性,从而筛选出针对不同癌症的潜在靶点㊂3.2　诱导TAMs向抗肿瘤的表型极化　据上所述, TAM包括M1型和M2型,两者的极化受细胞因子等因素决定㊂因此,可以通过诱导TAMs分化为M1型巨噬细胞,使其成为抗肿瘤的巨噬细胞㊂一是通过补充Th1型细胞因子或者干扰诱导M2型巨噬细胞极化的途径;另外,通过引入TLR激动剂激活NF⁃κB途径[28]㊂已知LPS㊁IFN⁃γ及GM⁃CSF为M1型巨噬细胞激活的主要诱导物㊂在卵巢癌患者中, IFN⁃α和IFN⁃γ为代表的免疫疗法,具有一定的治疗前景,但其治疗潜力尚不清楚㊂除了引入Th1细胞因子或TLR配体外,通过激活共刺激分子如CD40来刺激免疫应答已经显示出有希望的结果,而且在完全人源化的CD40激动剂抗体联合吉西他滨治疗中晚期胰腺癌的临床试验已经完成,且耐受性良好[29]㊂在动物实验中,给小鼠使用激动性抗CD40抗体后,发现肿瘤微环境中M2型巨噬细胞向M1型表型转化,表现为IL⁃12的分泌显著增加,并获得抗原呈递能力,肿瘤体积也减小[29⁃32]㊂S100A9和HDAC4的一种小分子抑制剂Tasquinimod也可以增加肿瘤组织内IL⁃12的分泌量,抑制新血管形成和M2型TAM的浸润,且使M1型巨噬细胞增加[33,34]㊂富组氨酸糖蛋白(Histidine rich glycoprotein,HRG)下调VEGF家族成员胎盘生长因子(Placental growth factor,PLGF)促进抗肿瘤免疫应答和肿瘤血管的正常化,使M2型巨噬细胞极化为M1型巨噬细胞㊂铜绿假单胞菌(绿脓杆菌)甘露糖敏感血凝菌毛株(Pseudomonas aeruginosa⁃mannose sensitive hemagglutinin,PA⁃MSHA)能上调M1型巨噬细胞相关基因的表达水平,促进巨噬细胞向M1型极化㊂另一方面,PA⁃MSHA可以下调M2型相关基因的表达,抑制小鼠膀胱癌细胞增殖㊁侵袭及转移㊂该项研究显示了PA⁃MSHA在TAMs靶向治疗膀胱癌中具有一定潜在价值[35]㊂STAT3与M2型TAM的极化及功能密切相关,Cheng等[36]首先描述了靶向STAT3可抑制M2型TAM的功能,并使荷瘤小鼠的免疫耐受性T细胞恢复免疫应答能力㊂涉及M2巨噬细胞分化的另一个途径是STAT6途径㊂Binnemars等[37]报道,使用AS1517499抑制STAT6磷酸化,可使巨噬细胞向M1表型极化㊂Pyonteck 等[38]报道,CSF⁃1R抑制剂BLZ945虽不能有效清除TAM,但可有效抑制胶质细胞瘤生长,其机制是BLZ945可促进胶质瘤细胞分泌GM⁃CSF及IFN⁃γ,从而诱导TAM向M1型转化㊂因此,针对M2型巨噬细胞向M1型巨噬细胞极化过程中的关键靶点,可以设计不同的治疗方案,以寻求潜在医疗价值㊂3.3　耗竭TAMs　目前,实现这一目标最有效的方法是使用对巨噬细胞有毒性的化合物㊂常用的药物是双膦酸盐,包括氯膦酸盐㊁唑来膦酸和曲贝替定[39]㊂有实验表明,载有氯膦酸盐的脂质体导致TAMs降低,从而导致肿瘤细胞生长的降低[40]㊂使用唑来膦酸与STAT3抑制剂索拉非尼的组合在肝细胞癌的裸鼠异种移植模型中显示可显著抑制肿瘤生长㊁转移和血管生成[41]㊂曲贝替定是提取自海洋生物加勒比海鞘的一种生物碱,对巨噬细胞和TAMs具有选择性细胞毒性,同时不损伤其他免疫细胞,因而具有抗肿瘤活性[42],在欧洲由EMEA批准用于治疗肉瘤和卵巢癌㊂除此之外,Cieslewicz 等[43]通过噬菌体肽库筛选技术得到了一种名为M2pep的肽㊂这种肽能够识别并选择性结合荷瘤小鼠体内的M2型巨噬细胞,从而达到耗竭TAMs的目的㊂3.4　阻断TAMs的促肿瘤功能　主要为阻断TAMs 的免疫抑制功能和抑制TAMs的促血管生成作用㊂膀胱癌中使用mPGES1和COX2的药物抑制剂或前列腺素脱氢酶,可抑制前列腺素2的生成,从而有效降低PD⁃L1的表达和减弱TAMs的免疫抑制功能[44]㊂此外,采用表达VEGFR⁃3的腺病毒可以阻断VEGF⁃C/D信号通路,从而抑制TAMs的促血管生成作用[45]㊂4　展望肿瘤为了逃避免疫监视作用,通过分泌特定的因子募集巨噬细胞到肿瘤组织,诱导巨噬细胞向促瘤作用的M2极化,参与肿瘤的生长㊁迁移㊁肿瘤血管生成㊁抑制NK和CTL对肿瘤的杀伤㊁对抗放化疗的打击㊂因此,通过阻断巨噬细胞到达肿瘤组织㊁清除巨噬细胞㊁抑制肿瘤微环境的TAM的活化或再极化为抑瘤作用的M1型巨噬细胞等靶向巨噬细胞的策略,已成为肿瘤免疫研究领域的热点问题㊂但肿瘤治疗是一个系统工程,任何单一的疗法效果都很局限㊂因此,应根据不同类型的肿瘤,将巨噬细胞靶向策略与目前常用的放化疗㊁抗肿瘤血管㊁小分子靶向药㊁免疫卡控点等多种疗法进行联合,以期达到最佳的个体化治疗效果㊂参考文献:[1]　Morrison C.Immuno⁃oncologists eye up macrophage targets[J].Nat Rev Drug Discov,2016,15(6):373⁃374.[2]　Sica A,Mantovani A.Macrophage plasticity and polarization:invivo veritas[J].J Clin Invest,2012,122(3):787⁃795. 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