苏鹏飞;于健春;
SU Pengfei;YU Jianchun;Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College;

• 1:中国医学科学院北京协和医院基本外科

摘要(Abstract)：

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。
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.

关键词(KeyWords)： 肿瘤相关巨噬细胞;恶性肿瘤;耐药;治疗
tumor-associated macrophages;malignant tumors;drug-resistance;treatment

Abstract:

Keywords:

基金项目(Foundation): 北京市科学技术委员会基金(D171100006517002)~~

作者(Authors): 苏鹏飞;于健春;
SU Pengfei;YU Jianchun;Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College;

参考文献(References)：

• [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.
• [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.
• [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.
• [4] Takeya M,Komohara Y.Role of tumor-associated macrophages in human malignancies:friend or foe?[J].Pathol Int,2016,66:491- 505.
• [5] Wang M,Zhao J,Zhang L,et al.Role of tumor microenvironment in tumorigenesis[J].J Cancer,2017,8:761- 773.
• [6] Mills CD,Kincaid K,Alt JM,et al.M- 1/M- 2 macropha-ges and the Th1/Th2 paradigm[J].J Immunol,2000,164:6166- 6173.
• [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.
• [8] Schultze JL,Schmidt SV.Molecular features of macrophage activation[J].Semin Immunol,2015,27:416- 423.
• [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.
• [10] Ostuni R,Kratochvill F,Murray PJ,et al.Macrophages and cancer:from mechanisms to therapeutic implications[J].Trends Immunol,2015,36:229- 239.
• [11] Li X,Liu R,Su X,et al.Harnessing tumor-associated macrophages as aids for cancer immunotherapy[J].Mol Cancer,2019,18:177.
• [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.
• [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.
• [14] Sica A,Mantovani A.Macrophage plasticity and polariza-tion:in vivo veritas[J].J Clin Invest,2012,122:787- 795.
• [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.
• [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.
• [17] Kowal J,Kornete M,Joyce JA.Re-education of macro-phages as a therapeutic strategy in cancer[J].Immunotherapy,2019,11:677- 689.
• [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.
• [19] Yin Y,Yao S,Hu Y,et al.The immune- microenviron-ment confers chemoresistance of colorectal cancer through macrophage-derived IL6[J].Clin Cancer Res,2017,23:7375- 7387.
• [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.
• [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.
• [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.
• [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.
• [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.
• [26] Li D,Ji H,Niu X,et al.Tumor-associated macrophages secrete CC-chemokine ligand 2 and induce tamoxifen resis-tance by activating PI3K/Akt/mTOR in breast cancer[J].Cancer Sci,2020,111:47- 58.
• [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.
• [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.
• [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.
• [31] Stockmann C,Doedens A,Weidemann A,et al.Deletion of vascular endothelial growth factor in myeloid cells accelera-tes tumorigenesis[J].Nature,2008,456:814- 818.
• [32] De Palma M,Lewis CE.Cancer:Macrophages limit chemo-therapy[J].Nature,2011,472:303- 304.
• [33] Li Y,Weng Y,Zhong L,et al.VEGFR3 inhibition chemo-sensitizes lung adenocarcinoma A549 cells in the tumor-associated macrophage microenvironment through upregulation of p53 and PTEN[J].Oncol Rep,2017,38:2761- 2773.
• [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.
• [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.
• [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.
• [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.
• [38] Larionova I,Cherdyntseva N,Liu T,et al.Interaction of tumor-associated macrophages and cancer chemotherapy[J].Oncoimmunology,2019,8:1596004.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [46] Lederman MM,Sieg SF.CCR5 and its ligands:a new axis of evil?[J].Nat Immunol,2007,8:1283- 1285.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.