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Tumour-Associated Macrophages pp 153–165Cite as

NF-KappaB-Mediated Regulation of Tumour-Associated Macrophages: Mechanisms and Significance

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Abstract

Smoldering inflammation is a component of the tumor microenvironment and represents the seventh hallmark of cancer. Tumor-associated macrophages (TAM) have served as a paradigm for cancer-promoting inflammation. TAM orchestrate various aspects of cancer, including: diversion and skewing of adaptive responses, cell growth; angiogenesis, matrix deposition and remodeling, the construction of a metastatic niche and actual metastasis, and response to hormones and chemotherapeutic agents. Recent studies on human and murine tumors indicate that TAM show a remarkable degree of plasticity and functional heterogeneity, during tumor development. Evidence is accumulating for a “switch” in macrophage phenotypes during the course of tumor progression. Whereas the functions of classically activated, “M1” macrophages during chronic inflammation appear to predispose a given tissue to tumor initiation, in established tumors macrophages exhibit mainly the alternatively activated, “M2” phenotype and resemble “tolerant” macrophages and are engaged in immunosuppression and the promotion of tumor angiogenesis and metastasis.

Here we discuss the evidence suggesting that selected members of the NF-κB family of transcription factors play a central role in the functional reprogramming of TAM during the course of tumor progression. Finally, we discuss the implications of this phenomenon for anti-cancer therapies aimed at prompting TAM to mount an effective antitumor response.

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References

  • Allavena P, Garlanda C, Borrello MG, Sica A, Mantovani A (2008) Pathways connecting inflammation and cancer. Curr Opin Genet Dev 18:3–10

    Article  PubMed  CAS  Google Scholar 

  • Andreu P, Johansson M, Affara NI, Pucci F, Tan T, Junankar S, Korets L, Lam J, Tawfik D, DeNardo DG et al (2010) FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17(2):121–134

    Article  PubMed  CAS  Google Scholar 

  • Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P et al (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050–1059

    Article  PubMed  CAS  Google Scholar 

  • Aspord C, Pedroza-Gonzalez A, Gallegos M, Tindle S, Burton EC, Su D, Marches F, Banchereau J, Palucka AK (2007) Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4+ T cells that facilitate tumor development. J Exp Med 204:1037–1047

    Article  PubMed  CAS  Google Scholar 

  • Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545

    Article  PubMed  CAS  Google Scholar 

  • Berek JS, Schultes BC, Nicodemus CF (2003) Biologic and immunologic therapies for ovarian cancer. J Clin Oncol 21:168s–174s

    Article  PubMed  Google Scholar 

  • Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A, Sironi M, Bottazzi B, Doni A, Bronte V, Pasqualini F et al (2006) A distinct and unique transcriptional programme expressed by tumor-associated macrophages: defective NF-kB and enhanced IRF-3/STAT1 activation. Blood 107:2112–2122

    Article  PubMed  CAS  Google Scholar 

  • Bonizzi G, Karin M (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25:280–288

    Article  PubMed  CAS  Google Scholar 

  • Cavaillon JM, Adib-Conquy M (2006) Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Crit Care 10:233

    Article  PubMed  Google Scholar 

  • Cavaillon JM, Adrie C, Fitting C, Adib-Conquy M (2005) Reprogramming of circulatory cells in sepsis and SIRS. J Endotoxin Res 11:311–320

    PubMed  CAS  Google Scholar 

  • Chen K, Huang J, Gong W, Iribarren P, Dunlop NM, Wang JM (2007) Toll-like receptors in inflammation, infection and cancer. Int Immunopharmacol 7:1271–1285

    Article  PubMed  CAS  Google Scholar 

  • Colombo MP, Mantovani A (2005) Targeting myelomonocytic cells to revert inflammation-dependent cancer promotion. Cancer Res 65:9113–9116

    Article  PubMed  CAS  Google Scholar 

  • Colombo N, Peccatori F, Paganin C, Bini S, Brandely M, Mangioni C, Mantovani A, Allavena P (1992) Anti-tumor and immunomodulatory activity of intraperitoneal IFN-gamma in ovarian carcinoma patients with minimal residual tumor after chemotherapy. Int J Cancer 51:42–46

    Article  PubMed  CAS  Google Scholar 

  • Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  PubMed  CAS  Google Scholar 

  • De Palma M, Murdoch C, Venneri MA, Naldini L, Lewis CE (2007) Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends Immunol 28:519–524

    Article  PubMed  Google Scholar 

  • de Visser KE, Korets LV, Coussens LM (2005) De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7:411–423

    Article  PubMed  Google Scholar 

  • DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, Coussens LM (2009) CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16:91–102

    Article  PubMed  CAS  Google Scholar 

  • Duluc D, Corvaisier M, Blanchard S, Catala L, Descamps P, Gamelin E, Ponsoda S, Delneste Y, Hebbar M, Jeannin P (2009) Interferon-gamma reverses the immunosuppressive properties and prevents the generation of human tumor-associated macrophages. Int J Cancer 125(2):367–373

    Article  PubMed  CAS  Google Scholar 

  • Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991–998

    Article  PubMed  CAS  Google Scholar 

  • Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ (2009) Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15:35–44

    Article  PubMed  CAS  Google Scholar 

  • Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS, Alberlda SM (2009) Polarization of tumor-associated neutrophil (TAN) phenotype by TGF-beta: “N1” versus “N2” TAN – a new paradigm? Cancer Cell 16:183–194

    Article  PubMed  CAS  Google Scholar 

  • Ghassabeh GH, De Baetselier P, Brys L, Noel W, Van Ginderachter JA, Meerschaut S, Beschin A, Brombacher F, Raes G (2006) Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo in different pathologic conditions. Blood 108:575–583

    Article  PubMed  CAS  Google Scholar 

  • Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, Vermaelen K, Panaretakis T, Mignot G, Ullrich E et al (2009) Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 15:1170–1178

    Article  PubMed  CAS  Google Scholar 

  • Ghosh P, Sica A, Young HA, Ye J, Franco JL, Wiltrout RH, Longo DL, Rice NR, Komschlies KL (1994) Alterations in NF kappa B/Rel family proteins in splenic T-cells from tumor-bearing mice and reversal following therapy. Cancer Res 54:2969–2972

    PubMed  CAS  Google Scholar 

  • Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF, Karin M (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:285–296

    Article  PubMed  CAS  Google Scholar 

  • Guiducci C, Vicari AP, Sangaletti S, Trinchieri G, Colombo MP (2005) Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res 65:3437–3446

    PubMed  CAS  Google Scholar 

  • Hagemann T, Wilson J, Kulbe H, Li NF, Leinster DA, Charles K, Klemm F, Pukrop T, Binder C, Balkwill FR (2005) Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. J Immunol 175:1197–1205

    PubMed  CAS  Google Scholar 

  • Hagemann T, Wilson J, Burke F, Kulbe H, Li NF, Pluddemann A, Charles K, Gordon S, Balkwill FR (2006) Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J Immunol 176:5023–5032

    PubMed  CAS  Google Scholar 

  • Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG, Robinson SC, Balkwill FR (2008) “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med 205:1261–1268

    Article  PubMed  CAS  Google Scholar 

  • Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827

    Article  PubMed  CAS  Google Scholar 

  • Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–436

    Article  PubMed  CAS  Google Scholar 

  • Kawai T, Akira S (2007) Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 13:460–469

    Article  PubMed  CAS  Google Scholar 

  • Kim S, Takahashi H, Lin W-W, Descargues P, Grivennikov S, Kim Y, Luo J-L, Karin M (2009) Carcinoma produced factors activate myeloid cells via TLR2 to stimulate metastasis. Nature 457:102–106

    Article  PubMed  CAS  Google Scholar 

  • Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, Niu G, Kay H, Mule J, Kerr WG et al (2005) Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11:1314–1321

    Article  PubMed  CAS  Google Scholar 

  • Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, Huang E, Finlayson E, Simeone D, Welling TH et al (2009) Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114:1141–1149

    Article  PubMed  CAS  Google Scholar 

  • Kuang DM, Wu Y, Chen N, Cheng J, Zhuang SM, Zheng L (2007) Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes. Blood 110:587–595

    Article  PubMed  CAS  Google Scholar 

  • Kulbe H, Thompson R, Wilson JL, Robinson S, Hagemann T, Fatah R, Gould D, Ayhan A, Balkwill F (2007) The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Res 67:585–592

    Article  PubMed  CAS  Google Scholar 

  • Kuroda E, Ho V, Ruschmann J, Antignano F, Hamilton M, Rauh MJ, Antov A, Flavell RA, Sly LM, Krystal G (2009) SHIP represses the generation of IL-3-induced M2 macrophages by inhibiting IL-4 production from basophils. J Immunol 183:3652–3660

    Article  PubMed  CAS  Google Scholar 

  • Liew FY, Xu D, Brint EK, O’Neill LA (2005) Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 5:446–458

    Article  PubMed  CAS  Google Scholar 

  • Loges S, Schmidt T, Tjwa M, Van Geyte K, Lievens D, Lutgens E, Vanhoute D, Borgel D, Plaisance S, Hoylaerts M et al (2010) Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6. Blood 115(11):2264–2273

    Article  PubMed  CAS  Google Scholar 

  • Luo Y, Zhou H, Krueger J, Kaplan C, Lee SH, Dolman C, Markowitz D, Wu W, Liu C, Reisfeld RA et al (2006) Targeting tumor-associated macrophages as a novel strategy against breast cancer. J Clin Invest 116:2132–2141

    Article  PubMed  CAS  Google Scholar 

  • Mantovani A (2009) Cancer: inflaming metastasis. Nature 457:36–37

    Article  PubMed  CAS  Google Scholar 

  • Mantovani A, Bottazzi B, Colotta F, Sozzani S, Ruco L (1992) The origin and function of tumor-associated macrophages. Immunol Today 13:265–270

    Article  PubMed  CAS  Google Scholar 

  • Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555

    Article  PubMed  CAS  Google Scholar 

  • Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686

    Article  PubMed  CAS  Google Scholar 

  • Mantovani A, Allavena P, Sica A, Balkwill F (2008a) Cancer-related inflammation. Nature 454:436–444

    Article  PubMed  CAS  Google Scholar 

  • Mantovani A, Romero P, Paluka A, Marincola F (2008b) Tumor immunity: effector response to tumor and the influence of the microenvironment. Lancet 371:771–783

    Article  PubMed  CAS  Google Scholar 

  • Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27:451–483

    Article  PubMed  CAS  Google Scholar 

  • Moore RJ, Owens DM, Stamp G, Arnott C, Burke F, East N, Holdsworth H, Turner L, Rollins B, Pasparakis M et al (1999) Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 5:828–831

    Article  PubMed  CAS  Google Scholar 

  • Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618–631

    Article  PubMed  CAS  Google Scholar 

  • Nickoloff BJ, Ben-Neriah Y, Pikarsky E (2005) Inflammation and cancer: is the link as simple as we think? J Invest Dermatol 124:x–xiv

    Article  PubMed  CAS  Google Scholar 

  • O’Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7:353–364

    Article  PubMed  Google Scholar 

  • Ostrand-Rosenberg S, Grusby MJ, Clements VK (2000) Cutting edge: STAT6-deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma. J Immunol 165:6015–6019

    PubMed  CAS  Google Scholar 

  • Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431:461–466

    Article  PubMed  CAS  Google Scholar 

  • Pollard JW (2009) Trophic macrophages in development and disease. Nat Rev Immunol 9:259–270

    Article  PubMed  CAS  Google Scholar 

  • Porta C, Rimoldi M, Raes G, Brys L, Ghezzi P, Di Liberto D, Dieli F, Ghisletti S, Natoli G, De Baetselier P et al (2009) Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB. Proc Natl Acad Sci USA 106:14978–14983

    Article  PubMed  CAS  Google Scholar 

  • Ritchie DS, Smyth MJ (2009) A new therapeutic target for leukemia comes to the surface. Cell 138:226–228

    Article  PubMed  CAS  Google Scholar 

  • Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M (2008) NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 453:807–811

    Article  PubMed  CAS  Google Scholar 

  • Roca H, Varsos ZS, Sud S, Craig MJ, Ying C, Pienta KJ (2009) CCL2 and IL-6 promote survival of human CD11b+ − peripheral blood mononuclear cells and induce M2-type macrophage polarization. J Biol Chem 284:34342–34354

    Article  PubMed  CAS  Google Scholar 

  • Saccani A, Schioppa T, Porta C, Biswas SK, Nebuloni M, Vago L, Bottazzi B, Colombo MP, Mantovani A, Sica A (2006) p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res 66:11432–11440

    Article  PubMed  CAS  Google Scholar 

  • Sica A, Bronte V (2007) Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 117:1155–1166

    Article  PubMed  CAS  Google Scholar 

  • Sica A, Saccani A, Bottazzi B, Polentarutti N, Vecchi A, van Damme J, Mantovani A (2000) Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. J Immunol 164:762–767

    PubMed  CAS  Google Scholar 

  • Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, Rimoldi M, Biswas SK, Allavena P, Mantovani A (2008) Macrophage polarization in tumour progression. Semin Cancer Biol 18:349–355

    Article  PubMed  CAS  Google Scholar 

  • Sierra JR, Corso S, Caione L, Cepero V, Conrotto P, Cignetti A, Piacibello W, Kumanogoh A, Kikutani H, Comoglio PM et al (2008) Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J Exp Med 205:1673–1685

    Article  PubMed  CAS  Google Scholar 

  • Smyth MJ, Dunn GP, Schreiber RD (2006) Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol 90:1–50

    Article  PubMed  CAS  Google Scholar 

  • Song L, Asgharzadeh S, Salo J, Engell K, Wu HW, Sposto R, Ara T, Silverman AM, DeClerck YA, Seeger RC et al (2009) Valpha24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages. J Clin Invest 119:1524–1536

    Article  PubMed  CAS  Google Scholar 

  • Torroella-Kouri M, Silvera R, Rodriguez D, Caso R, Shatry A, Opiela S, Ilkovitch D, Schwendener RA, Iragavarapu-Charyulu V, Cardentey Y et al (2009) Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated. Cancer Res 69:4800–4809

    Article  PubMed  CAS  Google Scholar 

  • Vaupel P (2008) Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist 13(Suppl 3):21–26

    Article  PubMed  CAS  Google Scholar 

  • Verma IM (2004) Nuclear factor (NF)-kappaB proteins: therapeutic targets. Ann Rheum Dis 63(Suppl 2):ii57–ii61

    Article  PubMed  CAS  Google Scholar 

  • Wallace KL, Marshall MA, Ramos SI, Lannigan JA, Field JJ, Strieter RM, Linden J (2009) NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-gamma and CXCR3 chemokines. Blood 114:667–676

    Article  PubMed  CAS  Google Scholar 

  • Wels J, Kaplan RN, Rafii S, Lyden D (2008) Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev 22:559–574

    Article  PubMed  CAS  Google Scholar 

  • Windbichler GH, Hausmaninger H, Stummvoll W, Graf AH, Kainz C, Lahodny J, Denison U, Muller-Holzner E, Marth C (2000) Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial. Br J Cancer 82:1138–1144

    Article  PubMed  CAS  Google Scholar 

  • Wyckoff JB, Wang Y, Lin EY, Li JF, Goswami S, Stanley ER, Segall JE, Pollard JW, Condeelis J (2007) Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67:2649–2656

    Article  PubMed  CAS  Google Scholar 

  • Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7:41–51

    Article  PubMed  CAS  Google Scholar 

  • Ziegler-Heitbrock HW, Petersmann I, Frankenberger M (1997) p50 (NF-kappa B1) is upregulated in LPS tolerant P388D1 murine macrophages. Immunobiology 198:73–80

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Istituto Clinico Humanitas IRCCS, via Manzoni 56, 20089, Rozzano, Italy

    Antonio Sica & Alberto Mantovani

  2. DiSCAFF, University of Piemonte Orientale A. Avogadro, 28100, Novara, Italy

    Antonio Sica

  3. Department of Translational Medicine, University of Milan, Milan, Italy

    Alberto Mantovani

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  1. Antonio Sica
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Correspondence to Antonio Sica .

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  1. Inserm-CNRS-Universitie de Mediteranee, Inflammation Biology Group, Centre d'Immunologie Marseille Luminy, Parc Scientifique de Luminy, Case 906, Marseille, Cedex 9, France

    Toby Lawrence

  2. Barts & The London Queen Mary's, School of Medicine & Dentistry, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom

    Thorsten Hagemann

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Sica, A., Mantovani, A. (2011). NF-KappaB-Mediated Regulation of Tumour-Associated Macrophages: Mechanisms and Significance. In: Lawrence, T., Hagemann, T. (eds) Tumour-Associated Macrophages. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0662-4_11

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