Progress in the Research on the Role of Tumor-associated Macrophages in Drug-resistance and Treatment of Tumors
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摘要: 肿瘤耐药的产生是肿瘤细胞与肿瘤微环境(tumor microenvironment, TME)相互作用的结果, 肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs)是TME中的主要免疫细胞, 在炎症微环境和肿瘤细胞的恶性表型之间发挥桥梁作用, 与肿瘤耐药和疾病进展密切相关, 其中M2型TAMs浸润则预示着不良的临床结局。本文主要针对TAMs参与肿瘤耐药的作用机制和治疗进展进行综述, 以期为减少肿瘤耐药、增强抗肿瘤治疗疗效提供参考。Abstract: The development of drug-resistance is the interactional result between tumor cells and tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are the main immune cells in TME, and act as the bridge between the inflammatory microenviroment and malignant phenotype of tumor cells. They are closely related to drug-resistance and tumor progression, and the infiltration of M2 macrophages indicates a poor clinical outcome. This paper reviews the progress in research of the role of TAMs in drug-resistance and treatment of tumors, providing references for decreasing drug-resistance and increasing the curative effects.
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Keywords:
- tumor-associated macrophages /
- malignant tumors /
- drug-resistance /
- treatment
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恶性肿瘤至今仍是严重危害人类健康并导致死亡的主要原因之一。据统计,2018年全球新增约1810万例恶性肿瘤患者和960万例恶性肿瘤死亡患者[1]。药物治疗是针对恶性肿瘤的有效治疗方法,然而,耐药的发生是引起治疗失败、肿瘤进展继而导致患者死亡的核心因素之一。关于肿瘤耐药的机制至今尚不明确,已有研究发现肿瘤耐药与药物靶蛋白的转变、药物代谢和解毒作用、抗凋亡和DNA损伤修复等机制相关[2-3]。近些年的研究进一步发现,肿瘤耐药是肿瘤细胞与肿瘤微环境(tumor microenvironment,TME)相互作用的结果。TME中含有多种基质细胞,肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)是其主要组成部分。作为具有可塑性的异质性群体,TME中的巨噬细胞在成熟分化过程中通过两种不同的激活途径呈现两种极化状态,即经典活化型(M1型)和替代活化型(M2型),其中M2型TAMs被认为在肿瘤耐药与疾病进展过程中发挥关键作用,预示着总生存期的缩减和不良预后[4]。本文就TAMs参与肿瘤耐药的作用机制和治疗进展进行综述,为探寻减少肿瘤耐药、增强抗肿瘤治疗疗效策略提供参考。
1. TAMs的生物学特性
1.1 TAMs与TME
肿瘤的发生与进展不仅取决于肿瘤细胞本身的恶性生物学特征,同时受整个TME生物学行为的影响。TME是一个复杂的整合系统,其中不仅有肿瘤细胞,还包括免疫活性细胞、成纤维细胞、血管内皮细胞、脂肪细胞、细胞外基质以及各种炎症介质和细胞因子等,其中免疫活性细胞是TME的主要组成部分,而巨噬细胞在免疫活性细胞群体中发挥主力军作用[5]。浸润于肿瘤组织或分布于TME中的巨噬细胞即为TAMs,其主要来源于常驻组织内的巨噬细胞,以及由血液循环中的单核细胞经多种趋化因子和生长因子募集并分化而来。
1.2 TAMs的异质性
肿瘤细胞以及包括TAMs在内的其他TME组分相互之间存在动态性和多相性作用,决定了TAMs存在异质性的特性。根据Mills团队所提出且被普遍接受的M1/M2二元极化模型(M1/M2 polarization model)理论,活化的巨噬细胞主要分为抗肿瘤效应的M1型(经典活化型)和促肿瘤效应的M2型(替代活化型)[6]。M1型TAMs是由γ干扰素(interferon-γ,IFN-γ)、粒细胞-巨噬细胞集落刺激因子(granulocyte-macrophage colony-stimulating factor,GM-CSF)和肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)等细胞因子诱导活化,可产生一氧化氮和活性氧簇,分泌白细胞介素(interleukin,IL)-1β、IL-6、IL-12、IL-23和诱导型一氧化氮合酶等各种促炎细胞因子,并具有抗原呈递能力,参与激活并启动机体的Th1型免疫应答,清除外来抗原并杀伤肿瘤细胞,从而发挥抗肿瘤作用[7-9]。而M2型TAMs主要由IL-4、IL-13、转化生长因子-β(transforming growth factor-β,TGF-β) 和巨噬细胞集落刺激因子(macrophage colony-stimulating factor,M-CSF)等细胞因子诱导活化,可高表达精氨酸酶-1(arginase-1,Arg-1)、甘露糖受体(CD206)和清道夫受体(CD163),产生IL-10、CC类趋化因子配体17(CC chemokine ligand 17,CCL17)、CCL18、CCL22等抗炎细胞因子,抑制炎症反应,参与Th2型免疫应答,对肿瘤进展起到促进作用[8, 10-11]。然而,随着单细胞转录组测序技术的发展,M1/M2二元极化模型受到光谱模型(spectrum model)的冲击,相较于大量细胞的转录组分析,单细胞转录组测序对细胞的异质性研究更具有针对性[12]。Xue等[13]通过对299个巨噬细胞转录组数据进行网络模型法分析,发现了至少9种不同的巨噬细胞激活途径。相信未来随着对TAMs转录组数据的不断发掘,TAMs亚型的分类将愈加全面。
1.3 TAMs的可塑性
TAMs具有显著可塑性,能够从一种极化状态转型至另一种极化状态。研究发现在肿瘤进展的初始阶段,TAMs主要以M1表型为优势特性,然而随着肿瘤的进展,TME中的肿瘤细胞或CD4+ T细胞来源的IL-4以及CSF-1、TGF-β和Arg-1等细胞因子表达增多,诱导M1型TAMs向M2型转化,逐步过渡为M2表型优势特性,进而通过促进分泌抗炎细胞因子、重塑基质和肿瘤血管生成等方式推进肿瘤耐药和进展[7, 14]。研究表明,磷脂酰肌醇-3-羟基酶-γ(phosphatidylinositol-3-hydroxy kinase-γ,PI3K-γ)通路和CSF-1在M2型TAMs极化过程中发挥重要作用,在胰腺导管腺癌模型中双重阻断PI3K-γ通路和CSF-1表达,可诱导TAMs由M2型向M1型转化[15-16]。信号传导与转录激活子6(signal transducer and activator of transcription 6,STAT6)可诱导TAMs向M2型转化,然而在小鼠模型中敲除STAT6后,TAMs展现出抗肿瘤效应的M1表型,具有类似效应的小分子包括CCL5、组蛋白去乙酰化酶(histone deacetyla-ses,HDACs)和酪氨酸蛋白激酶受体-2(tyrosine-protein kinase receptor-2,TPKR-2)等[17]。TAMs的可塑性让阻断M2型极化或M2型复极化为M1型的策略在抗肿瘤研究领域极具吸引力。公认的M1/M2二元极化模型立足于体外条件下,但由于TAMs的异质性和可塑性,TAMs在TME的不同信号刺激下发生着动态变化,体内环境的TAMs不可简单分为M1型和M2型。将单细胞转录组测序、空间转录组测序以及多路复用免疫组化等新兴技术应用于TAMs功能性生物标志物的研究,识别具有不同生物学作用的TAMs亚型,有助于将TAMs精准应用于肿瘤治疗中,此为TAMs相关研究方向之一[18]。
2. TAMs与肿瘤耐药
2.1 TAMs通过细胞因子参与肿瘤耐药
TAMs分泌的IL-6通过活化STAT3,下调抑癌分子miR-204-5p的水平,进而促使结直肠癌细胞抗凋亡能力增强,对5-氟尿嘧啶(5-fluorocrail,5-FU)和奥沙利铂产生抵抗[19]。Li等[20]研究发现,乳腺癌组织中的M2型TAMs与肿瘤细胞可通过IL-6的旁分泌回路促进肿瘤细胞对多柔比星(doxorubicin,DOX)耐药。IL-10主要由M2型TAMs诱导释放,具有活化STAT3的作用,同时上调原癌基因Bcl-2表达,进而降低紫杉醇对乳腺癌的杀伤力[21]。结直肠肿瘤中M2型TAMs分泌的CCL22可诱导肿瘤细胞发生上皮间质转化(epithelial-mesenchymal transition,EMT),并抑制半胱天冬酶介导的细胞凋亡,促使肿瘤细胞对5-FU产生耐药[22]。
胃癌病灶的缺氧环境激活缺氧诱导因子1α(hypoxia-inducible factor 1α,HIF1α),使高迁移率族蛋白B1(high mobility group protein B1,HMGB1)高表达,促使巨噬细胞向肿瘤迁移并产生生长分化因子15(growth differentiation factor 15,GDF15),加速胃癌细胞脂肪酸β的氧化进程,进而促使肿瘤耐药[23]。Ireland等[24]研究发现,M2型TAMs通过胰岛素样生长因子(insulin-like growth factor,IGF)诱导胰腺导管腺癌对吉西他滨产生耐药。组织蛋白酶属于半胱氨酸蛋白水解酶类,IL-4可活化TAMs来源的组织蛋白酶B和S,继而诱导肺癌、结肠癌和乳腺癌等肿瘤产生耐药性,可能与组织蛋白酶对药物靶蛋白的降解相关。
2.2 TAMs通过调节信号通路参与肿瘤耐药
乳腺癌组织中的巨噬细胞通过激活PI3K/AKT/生存素信号通路,抑制肿瘤细胞凋亡并诱导其发生自噬,从而降低乳腺癌细胞对DOX的敏感性[25]。Li等[26]在乳腺癌免疫治疗过程中发现TAMs通过CCL2/PI3K/AKT/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)信号通路增强肿瘤细胞的抗凋亡能力,进而对他莫昔芬产生耐药性。在胃癌化疗过程中,5-FU等常规化疗药物的使用诱导M2型TAMs发生葡萄糖转运蛋白3依赖型糖酵解过程,进而激活CCL8/Janus激酶1(Janus kinase1,JAK1)/STAT3信号通路,增强肿瘤细胞对5-FU的耐受性[27]。此外,亦有研究指出胃癌中的TAMs可通过激活HIF1α/白血病抑制因子(leukemia inhibitory factor,LIF)/STAT3信号通路诱导肿瘤细胞产生耐药[28]。
外泌体是细胞之间信号传递的载体,微RNA(microRNA,miRNA)作为一种小分子非编码RNA通常是外泌体所承载的对象,其在调控基因表达和传递生物信息方面发挥重要作用。在肺癌组织中,M2型TAMs来源的外泌体通过miR-3679-5p/NEDD4L/c-Myc信号通路促进肿瘤细胞发生有氧糖酵解,从而抑制肿瘤细胞凋亡,导致肿瘤对顺铂耐药[29]。Zhu等[30]研究发现,在卵巢癌动物移植瘤模型内注射TAMs来源的外泌体后,肿瘤细胞对顺铂产生耐受性,进一步探究发现其通过miR-223/人第10号染色体缺失的磷酸酶及张力蛋白同源物(phosphatase and tensin homolog deleted on chromosome ten,PTEN)/PI3K/AKT信号通路诱导肿瘤耐药,由此可见miRNA在TAMs调控肿瘤耐药的信号通路中发挥重要作用。
2.3 TAMs通过调节血管生成参与肿瘤耐药
缺氧和炎症环境是诱导肿瘤血管生成的关键因素,形成的肿瘤血管网进而维持肿瘤恶性进展。近期研究表明,恶性肿瘤中的免疫炎症细胞TAMs通过产生基质金属蛋白酶降解和重塑细胞外基质,并调节促血管生成因子的合成和释放,进而促进肿瘤血管的形成。Stockmann等[31]通过对肺癌皮下同种异体移植模型的研究发现,TAMs来源的血管内皮生长因子(vascular endothelial growth factor,VEGF)通过促进具有低血管密度、低迂曲度和低外膜细胞覆盖率特点的异常肿瘤血管网的形成,诱使肿瘤对环磷酰胺产生耐药,该研究与De Palma等[32]研究发现相一致,即TAMs通过分泌VEGF诱导肿瘤形成低灌注的异常血管,限制化疗药物进入肿瘤内部发挥抗肿瘤作用,显著降低化疗效果。在肺腺癌中,M2型TAMs可诱导VEGF-C及其受体VEGFR3高表达,促进肿瘤生长并降低抑癌基因p53和PTEN的表达,从而抑制肿瘤细胞凋亡,降低其对化疗药物的敏感性[33]。在卵巢癌抗VEGF治疗过程中,尽管TAMs中VEGFR1和VEGFR3的表达下降,但其仍可通过替代血管生成的途径增强肿瘤细胞对抗VEGF药物的耐受性[34]。
2.4 TAMs通过调节免疫微环境参与肿瘤耐药
免疫微环境与肿瘤的恶性进展、治疗效果和预后关系密切,肿瘤抑制药物可诱导肿瘤细胞呈现出抗原性质,促进免疫系统对其进行识别和清除,增强治疗的全身效应[35]。紫杉醇等化疗药物的使用诱导乳腺癌细胞产生CSF1和IL-34,募集巨噬细胞向TME浸润,继而抑制细胞毒性T淋巴细胞(cytotoxic T lymphocyte,CTL)的激活和增殖,削弱其抗肿瘤免疫能力,同时也降低了细胞毒类药物的抗肿瘤效果[36]。相反,CSF1的中和抗体可减少乳腺癌中TAMs的浸润,在一定程度上增强CTL的抗肿瘤免疫反应,从而提高化疗效力。在肺癌中,细胞毒类药物DOX通过激活核因子-κB(nuclear factor-κB,NF-κB)通路诱导肿瘤细胞产生IL-34,IL-34经增强子结合蛋白β(enhancer-binding protein β,EBPβ)介导,增强TAMs的免疫抑制和促肿瘤进展能力,抑制CTL应答并刺激调节性T淋巴细胞反应,从而协助肿瘤细胞发生免疫逃逸,并维持化疗过程中TME的内稳态,降低化疗效果[37]。
在肿瘤免疫治疗方面,通过提高CTL应答以及免疫检查点封锁等方式使肿瘤治疗取得显著效果,但仍有患者对程序性死亡[蛋白]-1及其配体-1(programmed death-1/ligand-1,PD-1/-L1)抗体的治疗无反应。研究发现,TAMs可表达PD-L1和CTL相关抗原4(cytotoxic T lymphocyte associated antigen-4,CTLA-4)配体,通过与T细胞上的PD-1和CTLA-4结合直接抑制T淋巴细胞免疫应答,降低免疫治疗效果[38]。
2.5 TAMs与肿瘤干细胞交互作用参与肿瘤耐药
肿瘤干细胞(cancer stem cells,CSCs)是一类具有自我更新、多向分化和肿瘤起始能力的细胞亚群,被认为是肿瘤发生、发展和耐药的关键。研究发现,M2型TAMs可诱导肿瘤细胞获得干细胞特性,从而促进肿瘤的恶性进展[39]。卵巢癌组织中的IL-17主要来源于TAMs和CD4+T淋巴细胞,其与具有干细胞表型的肿瘤细胞所表达的IL-17受体结合后,可激活NF-κB/p38丝裂原活化蛋白激酶(mitogen activated protein kinase,MAPK)信号通路,从而增强肿瘤细胞的干细胞特性,促进肿瘤进展和耐药[40]。M2型TAMs分泌的乳脂球蛋白表皮生长因子(milk fat globulin epidermal growth factor8,MFGE8)和IL-6协同激活转录因子STAT3,增强胰腺癌细胞的干细胞特性,并抑制CTL免疫应答,从而促进肿瘤耐药,而减少TAMs浸润后,肿瘤细胞的干细胞特性则显著下降[41]。同样,Yang等[42]在小细胞肺癌中发现,TAMs来源的IL-10通过激活JAK1/STAT1/NF-κB/Notch1信号通路,可显著增强肿瘤细胞的干细胞特性。
此外,有研究发现CSCs对TME中巨噬细胞的募集和极化具有一定促进作用。神经胶质瘤的CSCs分泌的骨膜蛋白可激活整合素αvβ3,募集周围血管中的巨噬细胞进入肿瘤病灶并向M2型极化,从而促进肿瘤进展和耐药[43]。Sainz等[44]发现胰腺癌的CSCs通过分泌TGF-β1、Nodal和激活素A(Activin A)诱导巨噬细胞向M2型转化,极化后的巨噬细胞产生人源性阳离子抗菌蛋白18,进而增强CSCs的干细胞特性。
3. TAMs在肿瘤治疗中的应用
基于TAMs在肿瘤耐药及恶性进展过程中的作用,以TAMs为靶点的治疗方法成为目前肿瘤治疗研究领域的热点,其与常用化疗药物、靶向治疗药物或免疫治疗药物等联合应用,有望降低肿瘤耐药并增强抗肿瘤疗效。当前以TAMs为靶点的抗肿瘤策略主要包括:(1)抑制TME中巨噬细胞的募集;(2)清除TME中的M2型TAMs;(3)调节TME中TAMs的极化,将M2型TAMs复极化为M1型;(4)TAMs介导抗肿瘤药物的递送。
CCL2-CCR2和CCL5-CCR5等趋化因子-趋化因子受体信号传导是募集巨噬细胞进入TME的主要途径,阻断此信号传导从而抑制巨噬细胞进入TME的方法已在临床前期模型和临床试验中进行效果评估。CCR2拮抗剂PF-04136309和MLN1202在临床前期动物模型中已被证实可降低TME中巨噬细胞的浸润程度,且CCR2拮抗剂与化疗方案FOLFIRINOX联合应用可增强胰腺肿瘤中CTL的免疫应答,提高化疗效力,从而抑制肿瘤进展[45]。研究发现,阻断CCL5-CCR5信号传导可改善乳腺癌、胃癌、结直肠癌和胰腺癌等肿瘤的治疗效果,CCR5拮抗剂可减轻胃癌的肿瘤负荷,抑制其腹膜转移,从而延长患者的生存期[46-49]。体外细胞试验表明,CCR5拮抗剂具有抑制胰腺癌细胞增殖并促进细胞凋亡的作用,且动物移植瘤模型也证实其可缓解胰腺癌发生肝转移[50]。由此可见,CCR2和CCR5拮抗剂等联合常规化疗药物在肿瘤治疗方面颇具前景。
靶向性清除M2型TAMs也展现出促进抗肿瘤免疫应答并抑制肿瘤生长的效果。Lee等[51]研究发现,杂合肽MEL-dKLA可靶向性结合M2型TAMs,诱导其发生线粒体凋亡,且对M1型TAMs、T淋巴细胞和树突状细胞等其他免疫细胞的亲和力较低,同时体内试验也证实其具有抑制肿瘤血管再生、减轻肿瘤负荷的作用。CSF-1在M2型TAMs极化过程中发挥重要作用,抗CSF-1受体抗体AFS98和M279通过阻断CSF-1信号传导,可有效清除乳腺癌中的M2型TAMs,抑制肿瘤细胞增殖并延长动物模型的生存期[15, 52]。
TAMs的可塑性促使M1型极化或M2型复极化为M1型的策略在肿瘤治疗研究领域颇具吸引力。科罗索酸(corosolic acid,CA)是一种具有抑制转录因子STAT3的化合物,经脂质体包装的CA与抗CD163抗体相结合可靶向作用于TAMs,下调IL-10表达的同时上调TNF-α表达,促进TAMs向M1型转化[53]。Rodell等[54]报道,Toll样受体7/8(toll-like receptor7/8,TLR7/8)拮抗剂R848可诱导巨噬细胞向M1型转化,经纳米颗粒携带的R848在多种肿瘤动物模型中可将M2型TAMs复极化为M1型,且与抗PD-1抗体联合应用可明显提升其抗肿瘤免疫能力。此外,外泌体可在细胞之间进行信号传递,使其成为转运基因工程药物或细胞毒性药物的理想载体。已有商业化设计可携带反义寡核苷酸的外泌体,可靶向性阻碍TAMs合成具有免疫抑制作用的转录因子STAT6、EBPβ等,进而显著上调TNF-α并下调IL-10的表达,促使M2型TAMs复极化为M1型。
由于巨噬细胞具有强大的吞噬能力,可在趋化因子的诱导下高效迁移至肿瘤病灶,且具有直接杀伤肿瘤细胞的能力,使得TAMs介导的抗肿瘤药物递送方式具有重要研究价值。有研究者将腹膜腔中的巨噬细胞与纳米颗粒或脂质体(liposome,LPO)形式的抗肿瘤药物共同孵育后,再将其注回动物模型体内,显著延长了药物循环半衰期,并增强其抗肿瘤效力,减少药物毒性[55]。在肺癌移植瘤动物模型中发现,通过TAMs介导递送LPO-DOX显示出更高的抗肿瘤效力,且具有低毒性优势[56]。
4. 小结
阐明肿瘤耐药途径和机制是目前肿瘤治疗领域面临的巨大挑战。近年来,随着肿瘤免疫相关研究的深入开展,人们逐渐认识到TAMs通过调节细胞因子、信号通路、免疫微环境、血管生成及肿瘤干细胞等途径促进肿瘤耐药,在肿瘤恶性进展中发挥重要作用。因此,基于TAMs促进肿瘤耐药的作用机制,研发设计以TAMs为靶点的抗肿瘤药物,联合应用化疗、靶向治疗或免疫治疗等药物,有望达到降低肿瘤药物耐受性并达到增强抗肿瘤疗效的目的。
作者贡献:苏鹏飞、于健春共同参与论文选题;苏鹏飞负责文献检索及论文撰写;于健春负责论文修订。利益冲突:所有作者均声明不存在利益冲突 -
[1] Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68: 394-424. DOI: 10.3322/caac.21492
[2] Zhang T, Yuan Q, Gu Z, et al. Advances of proteomics technologies for multidrug-resistant mechanisms[J]. Future Med Chem, 2019, 11: 2573-2593. DOI: 10.4155/fmc-2018-0507
[3] Taddia L, D'Arca D, Ferrari S, et al. Inside the biochemical pathways of thymidylate synthase perturbed by anticancer drugs: Novel strategies to overcome cancer chemoresistance[J]. Drug Resist Updat, 2015, 23: 20-54. DOI: 10.1016/j.drup.2015.10.003
[4] Takeya M, Komohara Y. Role of tumor-associated macrophages in human malignancies: friend or foe?[J]. Pathol Int, 2016, 66: 491-505. DOI: 10.1111/pin.12440
[5] Wang M, Zhao J, Zhang L, et al. Role of tumor microenvironment in tumorigenesis[J]. J Cancer, 2017, 8: 761-773. DOI: 10.7150/jca.17648
[6] Mills CD, Kincaid K, Alt JM, et al. M-1/M-2 macrophages and the Th1/Th2 paradigm[J]. J Immunol, 2000, 164: 6166-6173. DOI: 10.4049/jimmunol.164.12.6166
[7] Zhu J, Zhi Q, Zhou BP, et al. The role of tumor associated macrophages in the tumor microenvironment: mechanism and functions[J]. Anticancer Agents Med Chem, 2016, 16: 1133-1141. DOI: 10.2174/1871520616666160520112622
[8] Schultze JL, Schmidt SV. Molecular features of macrophage activation[J]. Semin Immunol, 2015, 27: 416-423. DOI: 10.1016/j.smim.2016.03.009
[9] Jeannin P, Paolini L, Adam C, et al. The roles of CSFs on the functional polarization of tumor-associated macrophages[J]. FEBS J, 2018, 285: 680-699. DOI: 10.1111/febs.14343
[10] Ostuni R, Kratochvill F, Murray PJ, et al. Macrophages and cancer: from mechanisms to therapeutic implications[J]. Trends Immunol, 2015, 36: 229-239. DOI: 10.1016/j.it.2015.02.004
[11] Li X, Liu R, Su X, et al. Harnessing tumor-associated macrophages as aids for cancer immunotherapy[J]. Mol Cancer, 2019, 18: 177. DOI: 10.1186/s12943-019-1102-3
[12] Wu K, Lin K, Li X, et al. Redefining tumor-associated Macrophage subpopulations and functions in the tumor microenvironment[J]. Front Immunol, 2020, 11: 1731. DOI: 10.3389/fimmu.2020.01731
[13] Xue J, Schmidt SV, Sander J, et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation[J]. Immunity, 2014, 40: 274-288. DOI: 10.1016/j.immuni.2014.01.006
[14] Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas[J]. J Clin Invest, 2012, 122: 787-795. DOI: 10.1172/JCI59643
[15] Candido JB, Morton JP, Bailey P, et al. CSF1R(+) macrophages sustain pancreatic tumor growth through T cell Suppression and maintenance of key gene programs that define the squamous subtype[J]. Cell Rep, 2018, 23: 1448-1460. DOI: 10.1016/j.celrep.2018.03.131
[16] Li M, Li M, Yang Y, et al. Remodeling tumor immune microenvironment via targeted blockade of PI3K-gamma and CSF-1/CSF-1R pathways in tumor associated macrophages for pancreatic cancer therapy[J]. J Control Release, 2020, 321: 23-35. DOI: 10.1016/j.jconrel.2020.02.011
[17] Kowal J, Kornete M, Joyce JA. Re-education of macrophages as a therapeutic strategy in cancer[J]. Immunotherapy, 2019, 11: 677-689. DOI: 10.2217/imt-2018-0156
[18] Sarode P, Zheng X, Giotopoulou GA, et al. Reprogramm-ing of tumor-associated macrophages by targeting beta-catenin/FOSL2/ARID5A signaling: A potential treatment of lung cancer[J]. Sci Adv, 2020, 6: eaaz6105. DOI: 10.1126/sciadv.aaz6105
[19] Yin Y, Yao S, Hu Y, et al. The immune-microenvironment confers chemoresistance of colorectal cancer through macrophage-derived IL6[J]. Clin Cancer Res, 2017, 23: 7375-7387. DOI: 10.1158/1078-0432.CCR-17-1283
[20] Li J, He K, Liu P, et al. Iron participated in breast cancer chemoresistance by reinforcing IL-6 paracrine loop[J]. Biochem Biophys Res Commun, 2016, 475: 154-160. DOI: 10.1016/j.bbrc.2016.05.064
[21] Yang C, He L, He P, et al. Increased drug resistance in breast cancer by tumor-associated macrophages through IL-10/STAT3/bcl-2 signaling pathway[J]. Med Oncol, 2015, 32: 352.
[22] Wei C, Yang CG, Wang SY, et al. M2 macrophages confer resistance to 5-fluorouracil in colorectal cancer through the activation of CCL22/PI3K/AKT signaling[J]. Onco Targets Ther, 2019, 12: 3051-3063. DOI: 10.2147/OTT.S198126
[23] Yu S, Li Q, Yu Y, et al. Activated HIF1alpha of tumor cells promotes chemoresistance development via recruiting GDF15-producing tumor-associated macrophages in gastric cancer[J]. Cancer Immunol Immun, 2020, 69: 1973-1987. DOI: 10.1007/s00262-020-02598-5
[24] Ireland L, Santos A, Ahmed MS, et al. Chemoresistance in pancreatic cancer is driven by stroma-derived insulin-like growth factors[J]. Cancer Res, 2016, 76: 6851-6863. DOI: 10.1158/0008-5472.CAN-16-1201
[25] Zhang M, Zhang H, Tang F, et al. Doxorubicin resistance mediated by cytoplasmic macrophage colony-stimulating factor is associated with switch from apoptosis to autophagic cell death in MCF-7 breast cancer cells[J]. Exp Biol Med (Maywood), 2016, 241: 2086-2093. DOI: 10.1177/1535370216660399
[26] Li D, Ji H, Niu X, et al. Tumor-associated macrophages secrete CC-chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer[J]. Cancer Sci, 2020, 111: 47-58. DOI: 10.1111/cas.14230
[27] He Z, Chen D, Wu J, et al. Yes associated protein 1 promotes resistance to 5-fluorouracil in gastric cancer by regulating GLUT3-dependent glycometabolism reprogramming of tumor-associated macrophages[J]. Arch Biochem Biophys, 2021, 702: 108838. DOI: 10.1016/j.abb.2021.108838
[28] Yu S, Li Q, Wang Y, et al. Tumor-derived LIF promotes chemoresistance via activating tumor-associated macrophages in gastric cancers[J]. Exp Cell Res, 2021, 406: 112734. DOI: 10.1016/j.yexcr.2021.112734
[29] Wang H, Wang L, Pan H, et al. Exosomes derived from macrophages enhance aerobic glycolysis and chemoresistance in lung cancer by stabilizing c-Myc via the inhibition of NEDD4L[J]. Front Cell Dev Biol, 2021, 8: 231-246.
[30] Zhu X, Shen H, Yin X, et al. Macrophages derived exosomes deliver miR-223 to epithelial ovarian cancer cells to elicit a chemoresistant phenotype[J]. J Exp Clin Cancer Res, 2019, 38: 81. DOI: 10.1186/s13046-019-1095-1
[31] Stockmann C, Doedens A, Weidemann A, et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis[J]. Nature, 2008, 456: 814-818. DOI: 10.1038/nature07445
[32] De Palma M, Lewis CE. Cancer: Macrophages limit chemotherapy[J]. Nature, 2011, 472: 303-304. DOI: 10.1038/472303a
[33] Li Y, Weng Y, Zhong L, et al. VEGFR3 inhibition chemosensitizes lung adenocarcinoma A549 cells in the tumor-associated macrophage microenvironment through upregulation of p53 and PTEN[J]. Oncol Rep, 2017, 38: 2761-2773. DOI: 10.3892/or.2017.5969
[34] Dalton HJ, Pradeep S, Mcguire M, et al. Macrophages facilitate resistance to anti-VEGF therapy by altered VEGFR expression[J]. Clin Cancer Res, 2017, 23: 7034-7046. DOI: 10.1158/1078-0432.CCR-17-0647
[35] Bracci L, Schiavoni G, Sistigu A, et al. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer[J]. Cell Death Differ, 2014, 21: 15-25. DOI: 10.1038/cdd.2013.67
[36] Denardo DG, Brennan DJ, Rexhepaj E, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy[J]. Cancer Discov, 2011, 1: 54-67. DOI: 10.1158/2159-8274.CD-10-0028
[37] Baghdadi M, Wada H, Nakanishi S, et al. Chemotherapy-induced IL-34 enhances immunosuppression by tumor-associated macrophages and mediates survival of chemoresistant lung cancer cells[J]. Cancer Res, 2016, 76: 6030-6042. DOI: 10.1158/0008-5472.CAN-16-1170
[38] Larionova I, Cherdyntseva N, Liu T, et al. Interaction of tumor-associated macrophages and cancer chemotherapy[J]. Oncoimmunology, 2019, 8: 1596004. DOI: 10.1080/2162402X.2019.1596004
[39] Vahidian F, Duijf P, Safarzadeh E, et al. Interactions between cancer stem cells, immune system and some environmental components: Friends or foes?[J]. Immunol Lett, 2019, 208: 19-29. DOI: 10.1016/j.imlet.2019.03.004
[40] Xiang T, Long H, He L, et al. Interleukin-17 produced by tumor microenvironment promotes self-renewal of CD133+ cancer stem-like cells in ovarian cancer[J]. Oncogene, 2015, 34: 165-176. DOI: 10.1038/onc.2013.537
[41] Mitchem JB, Brennan DJ, Knolhoff BL, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses[J]. Cancer Res, 2013, 73: 1128-1141. DOI: 10.1158/0008-5472.CAN-12-2731
[42] Yang L, Dong Y, Li Y, et al. IL-10 derived from M2 macrophage promotes cancer stemness via JAK1/STAT1/NF-kappaB/Notch1 pathway in non-small cell lung cancer[J]. Int J Cancer, 2019, 145: 1099-1110. DOI: 10.1002/ijc.32151
[43] Zhou W, Ke SQ, Huang Z, et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth[J]. Nat Cell Biol, 2015, 17: 170-182. DOI: 10.1038/ncb3090
[44] Sainz BJ, Alcala S, Garcia E, et al. Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment[J]. Gut, 2015, 64: 1921-1935. DOI: 10.1136/gutjnl-2014-308935
[45] Nywening TM, Belt BA, Cullinan DR, et al. Targeting both tumour-associated CXCR2(+) neutrophils and CCR2(+) macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma[J]. Gut, 2018, 67: 1112-1123. DOI: 10.1136/gutjnl-2017-313738
[46] Lederman MM, Sieg SF. CCR5 and its ligands: a new axis of evil?[J]. Nat Immunol, 2007, 8: 1283-1285. DOI: 10.1038/ni1207-1283
[47] Gao D, Cazares LH, Fish EN. CCL5-CCR5 interactions modulate metabolic events during tumor onset to promote tumorigenesis[J]. BMC Cancer, 2017, 17: 834. DOI: 10.1186/s12885-017-3817-0
[48] Halama N, Zoernig I, Berthel A, et al. Tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by anti-CCR5 therapy in cancer patients[J]. Cancer cell, 2016, 29: 587-601. DOI: 10.1016/j.ccell.2016.03.005
[49] Aldinucci D, Casagrande N. Inhibition of the CCL5/CCR5 axis against the progression of gastric cancer[J]. Int J Mol Sci, 2018, 19: 1477. DOI: 10.3390/ijms19051477
[50] Huang H, Zepp M, Georges RB, et al. The CCR5 antagonist maraviroc causes remission of pancreatic cancer liver metastasis in nude rats based on cell cycle inhibition and apoptosis induction[J]. Cancer Lett, 2020, 474: 82-93. DOI: 10.1016/j.canlet.2020.01.009
[51] Lee C, Jeong H, Bae Y, et al. Targeting of M2-like tumor-associated macrophages with a melittin-based pro-apoptotic peptide[J]. J Immunother Cancer, 2019, 7: 147. DOI: 10.1186/s40425-019-0610-4
[52] Hume DA, Macdonald KP. Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling[J]. Blood, 2012, 119: 1810-1820. DOI: 10.1182/blood-2011-09-379214
[53] Andersen MN, Etzerodt A, Graversen JH, et al. STAT3 inhibition specifically in human monocytes and macrophages by CD163-targeted corosolic acid-containing liposomes[J]. Cancer Immunol Immunother, 2019, 68: 489-502. DOI: 10.1007/s00262-019-02301-3
[54] Rodell CB, Arlauckas SP, Cuccarese MF, et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy[J]. Nat Biomed Eng, 2018, 2: 578-588. DOI: 10.1038/s41551-018-0236-8
[55] Tanei T, Leonard F, Liu X, et al. Redirecting transport of nanoparticle albumin-bound paclitaxel to macrophages enhances therapeutic efficacy against liver metastases[J]. Cancer Res, 2016, 76: 429-439. DOI: 10.1158/0008-5472.CAN-15-1576
[56] Choi J, Kim HY, Ju EJ, et al. Use of macrophages to deliver therapeutic and imaging contrast agents to tumors[J]. Biomaterials, 2012, 33: 4195-4203. DOI: 10.1016/j.biomaterials.2012.02.022
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