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浙江大学学报(医学版)  2018, Vol. 47 Issue (5): 558-563    DOI: 10.3785/j.issn.1008-9292.2018.10.17
综述     
肿瘤相关成纤维细胞对肿瘤免疫调控作用的研究进展
李高鹏(),何佳,王青青*()
浙江大学医学院免疫学研究所, 浙江 杭州 310058
Progress on cancer associated fibroblasts in tumor immunoregulation
LI Gaopeng(),HE Jia,WANG Qingqing*()
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
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摘要:

肿瘤相关成纤维细胞(CAF)是肿瘤微环境中的重要组分,它通过分泌多种生长因子、趋化因子以及蛋白酶,调控肿瘤微环境中固有免疫细胞和适应性免疫细胞的募集和功能的发挥。此外,CAF分泌的胞外基质在塑造肿瘤微环境免疫抑制特性以及低氧形成的过程中也发挥着重要的促进作用。本文综述了肿瘤微环境中CAF对固有免疫细胞和适应性免疫细胞的浸润以及功能发挥的调控机制,同时针对以CAF为靶细胞进行药物开发的相关问题进行了展望,为进一步研究CAF的功能和临床应用提供科学依据。

关键词: 肿瘤/免疫学成纤维细胞/免疫学综述    
Abstract:

Cancer associated fibroblasts (CAFs) are important components of the tumor microenvironment. Through secreting of multiple growth factors, cytokines and proteases, CAFs play a significant role in regulating the recruitment and function of various innate immune cells and adaptive immune cells in tumor microenvironment. In addition, extracellular matrix secreted by CAFs can also promote the formation of immunosuppression and hypoxia of tumor microenvironment. Here, we review the progress on CAFs in regulation of immune cells and tumor immunity.

Key words: Neoplasms/immunology    Fibroblasts/immunology    Review
收稿日期: 2018-04-14 出版日期: 2019-01-23
:  R392.12  
基金资助: 国家自然科学基金(81373115)
通讯作者: 王青青     E-mail: 21607033@zju.edu.cn;wqq@zju.edu.cn
作者简介: 李高鹏(1993-), 男, 硕士研究生, 主要从事肿瘤免疫学研究; E-mail:21607033@zju.edu.cn; https://orcid.org/0000-0003-1148-7267
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引用本文:

李高鹏,何佳,王青青. 肿瘤相关成纤维细胞对肿瘤免疫调控作用的研究进展[J]. 浙江大学学报(医学版), 2018, 47(5): 558-563.

LI Gaopeng,HE Jia,WANG Qingqing. Progress on cancer associated fibroblasts in tumor immunoregulation. J Zhejiang Univ (Med Sci), 2018, 47(5): 558-563.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2018.10.17        http://www.zjujournals.com/med/CN/Y2018/V47/I5/558

图 1  肿瘤相关成纤维细胞对肿瘤微环境中免疫细胞的调控作用
1 NEESSE A , MICHL P , FRESE K K et al. Stromal biology and therapy in pancreatic cancer[J]. Gut, 2011, 60 (6): 861- 868
doi: 10.1136/gut.2010.226092
2 KOONTONGKAEW S . The tumor microenvironment contribution to development, growth, invasion and metastasis of head and neck squamous cell carcinomas[J]. J Cancer, 2013, 4 (1): 66- 83
doi: 10.7150/jca.5112
3 ISHIMOTO T , MIYAKE K , NANDI T et al. Activation of transforming growth factor beta 1 signaling in gastric cancer-associated fibroblasts increases their motility, via expression of rhomboid 5 homolog 2, and ability to induce invasiveness of gastric cancer cells[J]. Gastroenterology, 2017, 153 (1): 191- 204.e16
doi: 10.1053/j.gastro.2017.03.046
4 KALLURI R . The biology and function of fibroblasts in cancer[J]. Nat Rev Cancer, 2016, 16 (9): 582- 598
doi: 10.1038/nrc.2016.73
5 MANTOVANI A , MARCHESI F , MALESCI A et al. Tumour-associated macrophages as treatment targets in oncology[J]. Nat Rev Clin Oncol, 2017, 14 (7): 399- 416
doi: 10.1038/nrclinonc.2016.217
6 ZHANG A , QIAN Y , YE Z et al. Cancer-associated fibroblasts promote M2 polarization of macrophages in pancreatic ductal adenocarcinoma[J]. Cancer Med, 2017, 6 (2): 463- 470
7 MATHEW E , BRANNON A L , DEL VECCHIO A et al. Mesenchymal stem cells promote pancreatic tumor growth by inducing alternative polarization of macrophages[J]. Neoplasia, 2016, 18 (3): 142- 151
doi: 10.1016/j.neo.2016.01.005
8 YEH C R , SLAVIN S , DA J et al. Estrogen receptor alpha in cancer associated fibroblasts suppresses prostate cancer invasion via reducing CCL5, IL6 and macrophage infiltration in the tumor microenvironment[J]. Mol Cancer, 2016, 15 (1): 7
9 MACE T A , AMEEN Z , COLLINS A et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner[J]. Cancer Res, 2013, 73 (10): 3007- 3018
doi: 10.1158/0008-5472.CAN-12-4601
10 ALLAOUI R , BERGENFELZ C , MOHLIN S et al. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers[J]. Nat Commun, 2016, 7 13050
doi: 10.1038/ncomms13050
11 YANG X , LIN Y , SHI Y et al. FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling[J]. Cancer Res, 2016, 76 (14): 4124- 4135
doi: 10.1158/0008-5472.CAN-15-2973
12 OHSHIO Y , HANAOKA J , KONTANI K et al. Tranilast inhibits the function of cancer-associated fibroblasts responsible for the induction of immune suppressor cell types[J]. Scand J Immunol, 2014, 80 (6): 408- 416
doi: 10.1111/sji.2014.80.issue-6
13 KHOSRAVI-MAHARLOOEI M , PAKYARI M , JALILI R B et al. Tolerogenic effect of mouse fibroblasts on dendritic cells[J]. Immunology, 2016, 148 (1): 22- 33
14 CHENG J T, DENG Y N, YI H M, et al. Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation[J/OL]. Oncogenesis, 2016, 5: e198.
15 DE MONTE L , RENI M , TASSI E et al. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer[J]. J Exp Med, 2011, 208 (3): 469- 478
doi: 10.1084/jem.20101876
16 LAKINS M A , GHORANI E , MUNIR H et al. Cancer-associated fibroblasts induce antigen-specific deletion of CD8(+) T cells to protect tumour cells[J]. Nat Commun, 2018, 9 (1): 948
17 FEIG C , JONES J O , KRAMAN M et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer[J]. Proc Natl Acad Sci U S A, 2013, 110 (50): 20212- 20217
doi: 10.1073/pnas.1320318110
18 HOWRYLAK J A , NAKAHIRA K . Inflammasomes:key mediators of lung immunity[J]. Annu Rev Physiol, 2017, 79 471- 494
doi: 10.1146/annurev-physiol-021115-105229
19 SHAFER-WEAVER K A , ANDERSON M J , STAGLIANO K et al. Cutting edge:tumor-specific CD8+ T cells infiltrating prostatic tumors are induced to become suppressor cells[J]. J Immunol, 2009, 183 (8): 4848- 4852
doi: 10.4049/jimmunol.0900848
20 SHEN C C , KANG Y H , ZHAO M et al. WNT16B from ovarian fibroblasts induces differentiation of regulatory T cells through beta-catenin signal in dendritic cells[J]. Int J Mol Sci, 2014, 15 (7): 12928- 12939
doi: 10.3390/ijms150712928
21 OZDEMIR B C , PENTCHEVA-HOANG T , CARSTENS J L et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival[J]. Cancer Cell, 2014, 25 (6): 719- 734
doi: 10.1016/j.ccr.2014.04.005
22 SEWELL-LOFTIN M K , BAYER S V H , CRIST E et al. Cancer-associated fibroblasts support vascular growth through mechanical force[J]. Sci Rep, 2017, 7 (1): 12574
doi: 10.1038/s41598-017-13006-x
23 ORIMO A , GUPTA P B , SGROI D C et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion[J]. Cell, 2005, 121 (3): 335- 348
24 YANG J , LU Y , LIN Y Y et al. Vascular mimicry formation is promoted by paracrine TGF-beta and SDF1 of cancer-associated fibroblasts and inhibited by miR-101 in hepatocellular carcinoma[J]. Cancer Lett, 2016, 383 (1): 18- 27
doi: 10.1016/j.canlet.2016.09.012
25 DE PALMA M , BIZIATO D , PETROVA T V . Microenvironmental regulation of tumour angiogenesis[J]. Nat Rev Cancer, 2017, 17 (8): 457- 474
doi: 10.1038/nrc.2017.51
26 LIN N N , WANG P , ZHAO D et al. Significance of oral cancer-associated fibroblasts in angiogenesis, lymphangiogenesis, and tumor invasion in oral squamous cell carcinoma[J]. J Oral Pathol Med, 2017, 46 (1): 21- 30
doi: 10.1111/jop.2017.46.issue-1
27 MCWHORTER F Y , DAVIS C T , LIU W F . Physical and mechanical regulation of macrophage phenotype and function[J]. Cell Mol Life Sci, 2015, 72 (7): 1303- 1316
doi: 10.1007/s00018-014-1796-8
28 BARKER H E , COX T R , ERLER J T . The rationale for targeting the LOX family in cancer[J]. Nat Rev Cancer, 2012, 12 (8): 540- 552
doi: 10.1038/nrc3319
29 KOBAYASHI N , MIYOSHI S , MIKAMI T et al. Hyaluronan deficiency in tumor stroma impairs macrophage trafficking and tumor neovascularization[J]. Cancer Res, 2010, 70 (18): 7073- 7083
doi: 10.1158/0008-5472.CAN-09-4687
30 NIELSEN S R , QUARANTA V , LINFORD A et al. Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis[J]. Nat Cell Biol, 2016, 18 (5): 549- 560
doi: 10.1038/ncb3340
31 MEYAARD L . The inhibitory collagen receptor LAIR-1(CD305)[J]. J Leukoc Biol, 2008, 83 (4): 799- 803
doi: 10.1189/jlb.0907609
32 SPRINGER N L , FISCHBACH C . Biomaterials approaches to modeling macrophage-extracellular matrix interactions in the tumor microenvironment[J]. Curr Opin Biotechnol, 2016, 40 16- 23
doi: 10.1016/j.copbio.2016.02.003
33 PICKUP M W , MOUW J K , WEAVER V M . The extracellular matrix modulates the hallmarks of cancer[J]. EMBO Rep, 2014, 15 (12): 1243- 1253
doi: 10.15252/embr.201439246
34 PRIES A R, CORNELISSEN A J, SLOOT A A, et al. Structural adaptation and heterogeneity of normal and tumor microvascular networks[J/OL]. PLoS Comput Biol, 2009, 5(5): e1000394.
35 BENTOVIM L , AMARILIO R , ZELZER E . HIF1 alpha is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development[J]. Development, 2012, 139 (23): 4473- 4483
doi: 10.1242/dev.083881
36 JEONG S K , KIM J S , LEE C G et al. Tumor associated macrophages provide the survival resistance of tumor cells to hypoxic microenvironmental condition through IL-6 receptor-mediated signals[J]. Immunobiology, 2017, 222 (1): 55- 65
doi: 10.1016/j.imbio.2015.11.010
37 CHIU D K , XU I M , LAI R K et al. Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26[J]. Hepatology, 2016, 64 (3): 797- 813
doi: 10.1002/hep.v64.3
38 ROBERTS E W , DEONARINE A , JONES J O et al. Depletion of stromal cells expressing fibroblast activation protein-alpha from skeletal muscle and bone marrow results in cachexia and anemia[J]. J Exp Med, 2013, 210 (6): 1137- 1151
doi: 10.1084/jem.20122344
39 BROKOPP C E , SCHOENAUER R , RICHARDS P et al. Fibroblast activation protein is induced by inflammation and degrades type Ⅰ collagen in thin-cap fibroatheromata[J]. Eur Heart J, 2011, 32 (21): 2713- 2722
doi: 10.1093/eurheartj/ehq519
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