Regulation of macrophage function in tumors: the multifaceted role of NF-κB

Blood - Tập 113 - Trang 3139-3146 - 2009
Thorsten Hagemann1, Subhra K. Biswas2, Toby Lawrence1, Antonio Sica3, Claire E. Lewis4
1Centre for Cancer and Inflammation, Institute of Cancer, Barts and the London School of Medicine and Dentistry, London, United Kingdom;
2Laboratory of Human Innate Immunity, Singapore Immunology Network, Biomedical Sciences Institutes, Agency for Science, Technology & Research, Singapore;
3Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, and DiSCAFF, University of Piemonte Orientale A Avogadro, Novara, Italy; and
4Academic Unit of Pathology, University of Sheffield Medical School, Sheffield, United Kingdom

Tóm tắt

Abstract

The pivotal role of tumor-associated macrophages (TAMs) in tumor progression is now well established. TAMs have been shown to influence multiple steps in tumor development including the growth, survival, invasion, and metastasis of tumor cells as well as angiogenesis and lymphangiogenesis in tumors. The molecular circuits that polarize TAMs toward such a protumoral phenotype are now the focus of intense investigation. The transcription factor, nuclear factor–κB (NF-κB), is a master regulator of many cellular processes and been shown to regulate various pathways that impact on the function of TAMs. Much evidence for this has come from the use of elegant transgenic murine tumor models in which modification of single components of the NF-κB signaling pathway has been shown to regulate the pro-tumor repertoire of TAMs. Here, we outline this evidence and attempt to reconcile the various views that have emerged recently over the exact role of NF-κB in this phenomenon.


Tài liệu tham khảo

Witz, 2008, Yin-yang activities and vicious cycles in the tumor microenvironment., Cancer Res, 68, 9, 10.1158/0008-5472.CAN-07-2917 Mantovani, 2008, Cancer-related inflammation., Nature, 454, 436, 10.1038/nature07205 Murdoch, 2008, The role of myeloid cells in the promotion of tumour angiogenesis., Nat Rev Cancer, 8, 618, 10.1038/nrc2444 Lewis, 2006, Distinct role of macrophages in different tumor microenvironments., Cancer Res, 66, 605, 10.1158/0008-5472.CAN-05-4005 Pollard, 2004, Tumour-educated macrophages promote tumour progression and metastasis., Nat Rev Cancer, 4, 71, 10.1038/nrc1256 Mantovani, 1992, The origin and function of tumor-associated macrophages., Immunol Today, 13, 265, 10.1016/0167-5699(92)90008-U Lin, 2006, Macrophages regulate the angiogenic switch in a mouse model of breast cancer., Cancer Res, 66, 11238, 10.1158/0008-5472.CAN-06-1278 Lin, 2001, Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy., J Exp Med, 193, 727, 10.1084/jem.193.6.727 Bingle, 2002, The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies., J Pathol, 196, 254, 10.1002/path.1027 Dave, 2004, Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells., N Engl J Med, 351, 2159, 10.1056/NEJMoa041869 Rosenwald, 2002, The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma., N Engl J Med, 346, 1937, 10.1056/NEJMoa012914 Taylor, 2003, Monocyte heterogeneity and innate immunity., Immunity, 19, 2, 10.1016/S1074-7613(03)00178-X Mosser, 2008, Exploring the full spectrum of macrophage activation., Nat Rev Immunol, 8, 958, 10.1038/nri2448 Gordon, 2003, Alternative activation of macrophages., Nat Rev Immunol, 3, 23, 10.1038/nri978 Mantovani, 2002, Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes., Trends Immunol, 23, 549, 10.1016/S1471-4906(02)02302-5 Mantovani, 2004, The chemokine system in diverse forms of macrophage activation and polarization., Trends Immunol, 25, 677, 10.1016/j.it.2004.09.015 Van Ginderachter, 2006, Classical and alternative activation of mononuclear phagocytes: picking the best of both worlds for tumor promotion., Immunobiology, 211, 487, 10.1016/j.imbio.2006.06.002 Biswas, 2008, Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms., J Immunol, 180, 2011, 10.4049/jimmunol.180.4.2011 Stout, 2004, Functional plasticity of macrophages: reversible adaptation to changing microenvironments., J Leukoc Biol, 76, 509, 10.1189/jlb.0504272 Kusmartsev, 2005, STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion., J Immunol, 174, 4880, 10.4049/jimmunol.174.8.4880 Tsai, 2007, Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth., Int J Radiat Oncol Biol Phys, 68, 499, 10.1016/j.ijrobp.2007.01.041 Balkwill, 2001, Inflammation and cancer: back to Virchow?, Lancet, 357, 539, 10.1016/S0140-6736(00)04046-0 Sinha, 2005, Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis., Cancer Res, 65, 11743, 10.1158/0008-5472.CAN-05-0045 Sica, 2000, Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages., J Immunol, 164, 762, 10.4049/jimmunol.164.2.762 Curiel, 2004, Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival., Nat Med, 10, 942, 10.1038/nm1093 Bronte, 2001, Tumor-induced immune dysfunctions caused by myeloid suppressor cells., J Immunother, 24, 431, 10.1097/00002371-200111000-00001 Nagaraj, 2008, Tumor escape mechanism governed by myeloid-derived suppressor cells., Cancer Res, 68, 2561, 10.1158/0008-5472.CAN-07-6229 Sinha, 2007, Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response., J Immunol, 179, 977, 10.4049/jimmunol.179.2.977 Sinha, 2007, Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells., Cancer Res, 67, 4507, 10.1158/0008-5472.CAN-06-4174 Bronte, 2003, L-arginine metabolism in myeloid cells controls T-lymphocyte functions., Trends Immunol, 24, 302, 10.1016/S1471-4906(03)00132-7 Kusmartsev, 2005, Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells., J Immunol, 175, 4583, 10.4049/jimmunol.175.7.4583 Kusmartsev, 2004, Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species., J Immunol, 172, 989, 10.4049/jimmunol.172.2.989 Huang, 2006, Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host., Cancer Res, 66, 1123, 10.1158/0008-5472.CAN-05-1299 Gallina, 2006, Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells., J Clin Invest, 116, 2777, 10.1172/JCI28828 Yang, 2004, Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis., Cancer Cell, 6, 409, 10.1016/j.ccr.2004.08.031 Sica, 2007, Altered macrophage differentiation and immune dysfunction in tumor development., J Clin Invest, 117, 1155, 10.1172/JCI31422 Hoffmann, 2003, Genetic analysis of NF-kappaB/Rel transcription factors defines functional specificities., EMBO J, 22, 5530, 10.1093/emboj/cdg534 Kawai, 2007, Signaling to NF-kappaB by Toll-like receptors., Trends Mol Med, 13, 460, 10.1016/j.molmed.2007.09.002 Balkwill, 2004, Cancer and the chemokine network., Nat Rev Cancer, 4, 540, 10.1038/nrc1388 O'Neill, 2006, How Toll-like receptors signal: what we know and what we don't know., Curr Opin Immunol, 18, 3, 10.1016/j.coi.2005.11.012 Colonna, 2007, TLR pathways and IFN-regulatory factors: to each its own., Eur J Immunol, 37, 306, 10.1002/eji.200637009 Kawai, 2005, Toll-like receptor downstream signaling., Arthritis Res Ther, 7, 12, 10.1186/ar1469 Ozato, 2002, Toll-like receptor signaling and regulation of cytokine gene expression in the immune system., Biotechniques, 66, 10.2144/Oct0208 Ohmori, 2001, Requirement for STAT1 in LPS-induced gene expression in macrophages., J Leukoc Biol, 69, 598, 10.1189/jlb.69.4.598 Vakkila, 2008, Coordinate NF-kappaB and STAT1 activation promotes development of myeloid type 1 dendritic cells., Scand J Immunol, 67, 260, 10.1111/j.1365-3083.2007.02068.x Taniguchi, 2001, IRF family of transcription factors as regulators of host defense., Annu Rev Immunol, 19, 623, 10.1146/annurev.immunol.19.1.623 Shuai, 2003, Regulation of JAK-STAT signalling in the immune system., Nat Rev Immunol, 3, 900, 10.1038/nri1226 Jiang, 2000, IL-4/IL-13 signaling beyond JAK/STAT., J Allergy Clin Immunol, 105, 1063, 10.1067/mai.2000.107604 Donnelly, 1999, The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes., J Interferon Cytokine Res, 19, 563, 10.1089/107999099313695 O'Shea, 2004, A new modality for immunosuppression: targeting the JAK/STAT pathway., Nat Rev Drug Discov, 3, 555, 10.1038/nrd1441 Greten, 2004, IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer., Cell, 118, 285, 10.1016/j.cell.2004.07.013 Karin, 2005, NF-kappaB: linking inflammation and immunity to cancer development and progression., Nat Rev Immunol, 5, 749, 10.1038/nri1703 Luedde, 2007, Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma., Cancer Cell, 11, 119, 10.1016/j.ccr.2006.12.016 Maeda, 2005, IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis., Cell, 121, 977, 10.1016/j.cell.2005.04.014 Pikarsky, 2004, NF-kappaB functions as a tumour promoter in inflammation-associated cancer., Nature, 431, 461, 10.1038/nature02924 Lawrence, 2007, Cancer: sex, cytokines, and cancer., Science, 317, 51, 10.1126/science.1146052 Balkwill, 2005, Smoldering and polarized inflammation in the initiation and promotion of malignant disease., Cancer Cell, 7, 211, 10.1016/j.ccr.2005.02.013 Lin, 2007, A cytokine-mediated link between innate immunity, inflammation, and cancer., J Clin Invest, 117, 1175, 10.1172/JCI31537 Dinapoli, 1996, The altered tumoricidal capacity of macrophages isolated from tumor-bearing mice is related to reduce expression of the inducible nitric oxide synthase gene., J Exp Med, 183, 1323, 10.1084/jem.183.4.1323 Biswas, 2006, A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation)., Blood, 107, 2112, 10.1182/blood-2005-01-0428 Hagemann, 2006, Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype., J Immunol, 176, 5023, 10.4049/jimmunol.176.8.5023 Hagemann, 2008, “Re-educating” tumor-associated macrophages by targeting NF-kappaB., J Exp Med, 205, 1261, 10.1084/jem.20080108 Saccani, 2006, p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance., Cancer Res, 66, 11432, 10.1158/0008-5472.CAN-06-1867 Bohuslav, 1998, Regulation of an essential innate immune response by the p50 subunit of NF-kappaB., J Clin Invest, 102, 1645, 10.1172/JCI3877 Colombo, 2005, Targeting myelomonocytic cells to revert inflammation-dependent cancer promotion., Cancer Res, 65, 9113, 10.1158/0008-5472.CAN-05-2714 Guiducci, 2005, Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection., Cancer Res, 65, 3437, 10.1158/0008-5472.CAN-04-4262 Swann, 2008, Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis., Proc Natl Acad Sci U S A, 105, 652, 10.1073/pnas.0708594105 Fong, 2008, An antiinflammatory role for IKKbeta through the inhibition of “classical” macrophage activation., J Exp Med, 205, 1269, 10.1084/jem.20080124 Hagemann, 2005, Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK., J Immunol, 175, 1197, 10.4049/jimmunol.175.2.1197 Kawai, 2005, Pathogen recognition with Toll-like receptors., Curr Opin Immunol, 17, 338, 10.1016/j.coi.2005.02.007 Thomas, 2006, Contribution of interferon-beta to the murine macrophage response to the toll-like receptor 4 agonist, lipopolysaccharide., J Biol Chem, 281, 31119, 10.1074/jbc.M604958200 Tomczak, 2003, NF-kappa B is required within the innate immune system to inhibit microflora-induced colitis and expression of IL-12 p40., J Immunol, 171, 1484, 10.4049/jimmunol.171.3.1484 Balkwill, 1987, Evidence for tumour necrosis factor/cachectin production in cancer., Lancet, 2, 1229, 10.1016/S0140-6736(87)91850-2 Nawroth, 1988, Tumor necrosis factor/cachectin-induced intravascular fibrin formation in meth A fibrosarcomas., J Exp Med, 168, 637, 10.1084/jem.168.2.637 Wu, 2004, Long-term suppression of tumor growth by TNF requires a Stat1- and IFN regulatory factor 1-dependent IFN-gamma pathway but not IL-12 or IL-18., J Immunol, 172, 3243, 10.4049/jimmunol.172.5.3243 Ghassabeh, 2006, Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo during different pathologies., Blood, 108, 575, 10.1182/blood-2005-04-1485 Mantovani, 2005, Macrophage polarization comes of age., Immunity, 23, 344, 10.1016/j.immuni.2005.10.001 Elgert, 1998, Tumor-induced immune dysfunction: the macrophage connection., J Leukoc Biol, 64, 275, 10.1002/jlb.64.3.275 Tu, 2008, Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice., Cancer Cell, 14, 408, 10.1016/j.ccr.2008.10.011 Andersson, 2001, Novel candidate genes for atherosclerosis are identified by representational difference analysis-based transcript profiling of cholesterol-loaded macrophages., Pathobiology, 69, 304, 10.1159/000064637 Thomas, 2000, Critical role of C/EBPdelta and C/EBPbeta factors in the stimulation of the cyclooxygenase-2 gene transcription by interleukin-1beta in articular chondrocytes., Eur J Biochem, 267, 6798, 10.1046/j.1432-1033.2000.01778.x Wadleigh, 2000, Transcriptional activation of the cyclooxygenase-2 gene in endotoxin-treated RAW 264.7 macrophages., J Biol Chem, 275, 6259, 10.1074/jbc.275.9.6259 Klimp, 2001, Expression of cyclooxygenase-2 and inducible nitric oxide synthase in human ovarian tumors and tumor-associated macrophages., Cancer Res, 61, 7305 Banerjee, 2006, Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells., Proc Natl Acad Sci U S A, 103, 3274, 10.1073/pnas.0511113103 Lawrence, 2001, Possible new role for NF-kappaB in the resolution of inflammation., Nat Med, 7, 1291, 10.1038/nm1201-1291 Tsan, 2004, Endogenous ligands of Toll-like receptors., J Leukoc Biol, 76, 514, 10.1189/jlb.0304127 Kuang, 2007, Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes., Blood, 110, 587, 10.1182/blood-2007-01-068031 Chen, 2007, Toll-like receptors in inflammation, infection and cancer., Int Immunopharmacol, 7, 1271, 10.1016/j.intimp.2007.05.016 Vaupel, 2006, Impact of hemoglobin levels on tumor oxygenation: the higher, the better?, Strahlenther Onkol, 182, 63, 10.1007/s00066-006-1543-7 Burke, 2003, Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy., Am J Pathol, 163, 1233, 10.1016/S0002-9440(10)63483-9 Murdoch, 2004, Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues., Blood, 104, 2224, 10.1182/blood-2004-03-1109 Rius, 2008, NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha., Nature, 453, 807, 10.1038/nature06905