肿瘤相关巨噬细胞的极化及其对肿瘤治疗的影响
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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。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。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。因此,靶向抑制M2型巨噬细胞分化、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。本文主要对巨噬细胞的极化、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。
Plasticity and diversity are important characteristics of macrophages. According to their different functions,macrophages are classified into the classic activated type,M1 type,and the alternative activated type,M2 type. Not only the inducers for M1 and M2 macrophages differentiation were different,but the phenotypes and functions of M1 and M2 macrophages were different. M2 macrophages exist in most of the tumor microenvironment. Furthermore,the M2 type 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 in tumor treatment.
Plasticity and diversity are important characteristics of macrophages. According to their different functions,macrophages are classified into the classic activated type,M1 type,and the alternative activated type,M2 type. Not only the inducers for M1 and M2 macrophages differentiation were different,but the phenotypes and functions of M1 and M2 macrophages were different. M2 macrophages exist in most of the tumor microenvironment. Furthermore,the M2 type 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 in tumor treatment.
引文
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[43]Ciesiewicz M,Tang J,Yu JL,et al.Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival[J].Proc Natl Acad Sci U S A,2013,110(40):15919-15924.
[44]Prima V,Kaliberova LN,Kaliberov S,et al.COX2/m PGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells[J].Proc Natl Acad Sci U S A,2017,114(5):1117-1122.
[45]Yang H,Chan K,Kim MJ,et al.Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer[J].Mol Cancer,2011,10(1):36.
[2]Sica A,Mantovani A.Macrophage plasticity and polarization:in vivo veritas[J].J Clin Invest,2012,122(3):787-795.
[3]Verreck FA,de Boer T,Langenberg DM,et al.Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2macrophages subvert immunity to(myco)bacteria[J].Proc Natl Acad Sci U S A,2004,101(13):4560-4565.
[4]Essandoh K,Li Y,Huo J,et al.miRNA-mediated macrophage polarization and its potential role in the regulation of inflammatory response[J].Shock,2016,46(2):122-131.
[5]Krausgruber T,Blazek K,Smallie T,et al.IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses[J].Nat Immunol,2011,12(3):231-238.
[6]Fleetwood AJ,Dinh H,Cook AD,et al.GM-CSF and M-CSF-dependent macrophage phenotypes display differential dependence on type I interferon signaling[J].J Leukoc Biol,2009,86(2):411-421.
[7]Feilong Wang,Song Zhang,Ryounghoon Jeon,et al.Interferon gamma induces reversible metabolic reprogramming of M1 macrophages to sustain cell viability and pro-inflammatory activity[J].EBioMedicine,2018,30:303-316.
[8]Wicks IP,Roberts AW.Targeting GM-CSF in inflammatory diseases[J].Nat Rev Rheumatol,2016,12(1):37-48.
[9]Becher B,Tugues S,Greter M.GM-CSF:From growth factor to central mediator of tissue inflammation[J].Immunity,2016,45(5):963-973.
[10]Martinez FO,Helming L,Gordon S.Alternative activation of macrophages:an immunologic functional perspective[J].Annu Rev Immunol,2009,27:451-483.
[11]Hao NB,LüMH,Fan YH,et al.Macrophages in tumor microenvironments and the progression of tumors[J].Clin Dev Immunol,2012,2012:948098.
[12]Rhee I.Diverse macrophages polarization in tumor microenvironment[J].Arch Pharm Res,2016,39(11):1588-1596.
[13]Ferrante CJ,Leibovich SJ.Regulation of macrophage polarization and wound healing[J].Adv Wound Care(New Rochelle),2012,1(1):10-16.
[14]Herrlich P.Cross-talk between glucocorticoid receptor and AP-1[J].Oncogene,2001,20(19):2465-2475.
[15]Pinhal-Enfield G,Ramanathan M,Hasko G,et al.An angiogenic switch in macrophages involving synergy between Toll-like receptors 2,4,7,and 9 and adenosine A(2A)receptors[J].Am JPathol,2003,163(2):711-721.
[16]Balkwill F,Mantovani A.Inflammation and cancer:Back to Virchow?[J].Lancet,2001,357:539-545.
[17]Qian BZ,Pollard JW.Macrophage diversity enhances tumor progression and metastasis[J].Cell,2010,141(1):39-51.
[18]Quail DF,Bowman RL,Akkari L,et al.The tumor microenvironment underlies acquired resistance to CSF1R inhibition in gliomas[J].Science,2016,352(6288):aad3018.
[19]Mu X,Shi W,Xu Y,et al.Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3signaling pathway in breast cancer[J].Cell Cycle,2018,17(4):428-438.
[20]Zheng X,Turkowski K,Mora J,et al.Redirecting tumor-associated macrophages to become tumoricidal effectors as a novel strategy for cancer therapy[J].Oncotarget,2017,8(29):48436-48452.
[21]Dijkgraaf EM,Heusinkveld M,Tummers B,et al.Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment[J].Cancer Res,2013,73(8):2480-2492.
[22]Challagundla KB,Wise PM,Neviani P,et al.Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy[J].J Natl Cancer Inst,2015,107(7):pii:djv135.
[23]Gazzaniga S,Bravo AI,Guglielmotti A,et al.Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft[J].J Invest Dermatol,2007,127(8):2031-2041.
[24]Moisan F,Francisco EB,Brozovic A,et al.Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers[J].Mol Oncol,2014,8(7):1231-1239.
[25]Nywening TM,Wang-Gillam A,Sanford DE,et al.Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer:a single-centre,open-label,dose-finding,nonrandomised,phase 1b trial[J].Lancet Oncol,2016,17(5):651-662.
[26]Maolake A,Izumi K,Shigehara K,et al.Tumor-associated macrophages promote prostate cancer migration through activation of the CCL22-CCR4 axis[J].Oncotarget,2017,8(6):9739-9751.
[27]Halama N,Zoernig,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(4):587-601.
[28]Tang X,Mo C,Wang Y,et al.Anti-tumour strategies aiming to target tumour-associated macrophages[J].Immunology,2013,138(2):93-104.
[29]Beatty GL,Chiorean EG,Fishman MP,et al.CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans[J].Science,2011,331(6024):1612-1616.
[30]Buhtoiarov IN,Lum H,Berke G,et al.CD40 ligation activates murine macrophages via an IFN-γ-dependent mechanism resulting in tumor cell destruction in vitro[J].Immunology,2005,174:6013-6022.
[31]Buhtoiarov IN,Lum HD,Berke G,et al.Synergistic activation of macrophages via CD40 and TLR9 results in T cell independent antitumor effects[J].J Immunol,2006,176(1):309-318.
[32]Jensen JL,Rakhmilevich A,Heninger E,et al.Tumoricidal effects of macrophage-activating immunotherapy in a murine model of relapsed/refractory multiple myeloma[J].Cancer Immunol Res,2015,3(8):881-890.
[33]Olsson A,Nakhle J,Sundstedt A,et al.Tasquinimod triggers an early change in the polarization of tumor associated macrophages in the tumor microenvironment[J].J Immunother Cancer,2015,3:53.
[34]Shen L,Sundstedt A,Ciesielski M,et al.Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models[J].Cancer Immunol Res,2015,3(2):136-148.
[35]Liu J,Duan X.PA-MSHA induces apoptosis and suppresses metastasis by tumor associated macrophages in bladder cancer cells[J].Cancer Cell Int,2017,17(1):76.
[36]Cheng F,Wang HW,Cuenca A,et al.A critical role for Stat3 signaling in immune tolerance[J].Immunity,2003,19(3):425-436.
[37]Binnemars PK,Bansal R,Storm G,et al.Targeting the STAT6pathway in tumor-associated macrophages reduced tumor growth and metastaticniche formation in breast cancer[J].FASEB J,2018,32(2):969-978.
[38]Pyonteck SM,Akkari L,Schuhmacher AJ,et al.CSF-1R inhibition alters macrophage polarization and blocks glioma progression[J].Nat Med,2013,19(10):1264-1272.
[39]Germano G,Frapolli R,Belgiovine C,et al.Role of macrophage targeting in the antitumor activity of trabectedin[J].Cancer Cell,2013,23(2):249-262.
[40]Wu X,Schulte BC,Zhou Y,et al.Depletion of M2-like tumor-associated macrophages delays cutaneous t-cell lymphoma development in vivo[J].J Investig Dermatol,2014,134(11):2814-2822.
[41]Zhang W,Zhu XD,Sun HC,et al.Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects[J].Clin Cancer Res,2010,16(13):3420-3430.
[42]Allavena P,Signorelli M,Chieppa M,et al.Anti-inflammatory properties of the novel antitumor agent yondelis(Trabectedin):inhibition of macrophage differentiation and cytokine production[J].Cancer Res,2005,65(7):2964-2971.
[43]Ciesiewicz M,Tang J,Yu JL,et al.Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival[J].Proc Natl Acad Sci U S A,2013,110(40):15919-15924.
[44]Prima V,Kaliberova LN,Kaliberov S,et al.COX2/m PGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells[J].Proc Natl Acad Sci U S A,2017,114(5):1117-1122.
[45]Yang H,Chan K,Kim MJ,et al.Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer[J].Mol Cancer,2011,10(1):36.