Macrophage polarization as a novel weapon in conditioning tumor microenvironment for bladder cancer: can we turn demons into gods?

  • C. Rubio
  • E. Munera-Maravilla
  • I. Lodewijk
  • C. Suarez-Cabrera
  • V. Karaivanova
  • R. Ruiz-Palomares
  • J. M. Paramio
  • M. Dueñas
Review Article
Part of the following topical collections:
  1. The Immune System and Cancer\Immunotherapy


Macrophages are major components of the immune infiltration in cancer where they can affect tumor behavior. In the bladder, they play important roles during the resolution of infectious processes and they have been associated with a worse clinical prognosis in bladder cancer. The present review focused on the characteristics of these important immune cells, not only eliciting an innate immune surveillance, but also on their importance during the cancer immunoediting process. We further discuss the potential of targeting macrophages for anticancer therapy, the current strategies and the state of the art as well as the foreseen role on combined therapies on the near future. This review shows how a comprehensive understanding of macrophages within the tumor should translate to better clinical outcome and new therapeutic strategies focusing especially on bladder cancer.


TAMs in cancer TAMs in bladder TAMs targeted therapy 



This study was funded by the following: FEDER cofounded MINECO Grant SAF2015-66015-R, Grant ISCIII-RETIC RD12/0036/0009, PIE 15/00076 and CB/16/00228 to Jesús M. Paramio.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study informed consent is not required.


  1. 1.
    Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5(12):953–64.CrossRefGoogle Scholar
  2. 2.
    Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–69.CrossRefGoogle Scholar
  3. 3.
    Mantovani A. Inflammation and cancer: the macrophage connection. Med Aires. 2007;67:6–8.Google Scholar
  4. 4.
    Ginhoux F, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841–5.CrossRefGoogle Scholar
  5. 5.
    Yona S, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38(1):79–91.CrossRefGoogle Scholar
  6. 6.
    Shen L, et al. M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma. Sci Rep. 2016;6(1):30347.CrossRefGoogle Scholar
  7. 7.
    Franklin RA, et al. The cellular and molecular origin of tumor-associated macrophages. Science. 2014;344(6186):921–5.CrossRefGoogle Scholar
  8. 8.
    Calderon B, et al. The pancreas anatomy conditions the origin and properties of resident macrophages. J Exp Med. 2015;212(10):1497–512.CrossRefGoogle Scholar
  9. 9.
    Sheng J, Ruedl C, Karjalainen K. Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells. Immunity. 2015;43(2):382–93.CrossRefGoogle Scholar
  10. 10.
    Foey AD (2014) Macrophages—masters of immune activation, suppression and deviation. In: Immune response activation. Rijeka, Croatia: InTech Publishing. ISBN 978-953-51-1374-4.Google Scholar
  11. 11.
    Lacerda Mariano L, Ingersoll MA. Bladder resident macrophages: Mucosal sentinels. Cell Immunol. 2018;330:136–41. Scholar
  12. 12.
    Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11(10):889–96.CrossRefGoogle Scholar
  13. 13.
    de Groot AE, Pienta KJ. Epigenetic control of macrophage polarization: implications for targeting tumor-associated macrophages. Oncotarget. 2018;9(29):20908–27.CrossRefGoogle Scholar
  14. 14.
    Self-Fordham JB, Naqvi AR, Uttamani JR, Kulkarni V, Nares S. MicroRNA: dynamic regulators of macrophage polarization and plasticity. Front Immunol. 2017;8:1062.CrossRefGoogle Scholar
  15. 15.
    Coley W, et al. Absence of DICER in monocytes and its regulation by HIV-1. J Biol Chem. 2010;285(42):31930–43.CrossRefGoogle Scholar
  16. 16.
    Graff JW, Dickson AM, Clay G, McCaffrey AP, Wilson ME. Identifying functional microRNAs in macrophages with polarized phenotypes. J Biol Chem. 2012;287(26):21816–25.CrossRefGoogle Scholar
  17. 17.
    Zhuang G, et al. A novel regulator of macrophage activation: miR-223 in obesity-associated adipose tissue inflammation. Circulation. 2012;125(23):2892–903.CrossRefGoogle Scholar
  18. 18.
    Ponomarev ED, Veremeyko T, Barteneva N, Krichevsky AM, Weiner HL. MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α-PU.1 pathway. Nat Med. 2011;17(1):64–70.CrossRefGoogle Scholar
  19. 19.
    Essandoh K, Li Y, Huo J, Fan G-C. MiRNA-mediated macrophage polarization and its potential role in the regulation of inflammatory response. Shock. 2016;46(2):122–31.CrossRefGoogle Scholar
  20. 20.
    Caescu CI, et al. Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21. Blood. 2015;125(8):e1–13. Scholar
  21. 21.
    Hu S, Zhu W, Zhang L-F, Pei M, Liu M-F. MicroRNA-155 broadly orchestrates inflammation-induced changes of microRNA expression in breast cancer. Cell Res. 2014;24(2):254–7.CrossRefGoogle Scholar
  22. 22.
    Mora-Bau G, Platt AM, van Rooijen N, Randolph GJ, Albert ML, Ingersoll MA. Macrophages subvert adaptive immunity to urinary tract infection. PLoS Pathog. 2015;11(7):e1005044.CrossRefGoogle Scholar
  23. 23.
    Schiwon M, et al. Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium. Cell. 2014;156(3):456–68.CrossRefGoogle Scholar
  24. 24.
    Negrete HO, Lavelle JP, Berg J, Lewis SA, Zeidel ML. Permeability properties of the intact mammalian bladder epithelium. Am J Physiol Physiol. 1996;271(4):F886–94.CrossRefGoogle Scholar
  25. 25.
    Gardiner RA, Seymour GJ, Lavin MF, Strutton GM, Gemmell E, Hazan G. Immunohistochemical analysis of the human bladder. Br J Urol. 1986;58(1):19–25.CrossRefGoogle Scholar
  26. 26.
    Lavin Y, et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell. 2014;159(6):1312–26.CrossRefGoogle Scholar
  27. 27.
    Guilliams M, Malissen B. A matter of perspective: moving from a pre-omic to a systems-biology vantage of monocyte-derived cell function and nomenclature. Immunity. 2016;44(1):5–6.CrossRefGoogle Scholar
  28. 28.
    Carey AJ, et al. Uropathogenic Escherichia coli engages CD14-dependent signaling to enable bladder-macrophage-dependent control of acute urinary tract infection. J Infect Dis. 2016;213(4):659–68.CrossRefGoogle Scholar
  29. 29.
    Ojalvo LS, Whittaker CA, Condeelis JS, Pollard JW, Koch DH. Gene expression analysis of macrophages that facilitate tumor invasion supports a role for wnt-signaling in mediating their activity in primary mammary tumors. J Immunol. 2010;184(2):702–12. Scholar
  30. 30.
    Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14(7):399–416.CrossRefGoogle Scholar
  31. 31.
    Pyonteck SM, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19(10):1264–72.CrossRefGoogle Scholar
  32. 32.
    DeNardo DG, et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 2009;16(2):91–102.CrossRefGoogle Scholar
  33. 33.
    Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008;8(8):618–31.CrossRefGoogle Scholar
  34. 34.
    Pello OM, et al. Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology. Blood. 2012;119(2):411–21. Scholar
  35. 35.
    Van Acker HH, Anguille S, Willemen Y, Smits EL, Van Tendeloo VF. Bisphosphonates for cancer treatment: mechanisms of action and lessons from clinical trials. Pharmacol Ther. 2016;158:24–40.CrossRefGoogle Scholar
  36. 36.
    Galletti G, et al. Targeting macrophages sensitizes chronic lymphocytic leukemia to apoptosis and inhibits disease progression. Cell Rep. 2016;14:1748–60.CrossRefGoogle Scholar
  37. 37.
    König S, et al. Depletion of cutaneous macrophages and dendritic cells promotes growth of basal cell carcinoma in mice. PLoS One. 2014;9(4):e93555.CrossRefGoogle Scholar
  38. 38.
    Clezardin P. Mechanisms of action of bisphosphonates in oncology: a scientific concept evolving from antiresorptive to anticancer activities. Bonekey Rep. 2013;2:267. Scholar
  39. 39.
    Zhang W, et al. Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin Cancer Res. 2010;16(13):3420–30.CrossRefGoogle Scholar
  40. 40.
    Ozanne J, Prescott AR, Clark K. The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases. Biochem J. 2015;465(2):271–9.CrossRefGoogle Scholar
  41. 41.
    Allavena P, et al. Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production. Cancer Res. 2005;65(7):2964–71.CrossRefGoogle Scholar
  42. 42.
    Bak SP, Walters JJ, Takeya M, Conejo-Garcia JR, Berwin BL. Scavenger receptor-A-targeted leukocyte depletion inhibits peritoneal ovarian tumor progression. Cancer Res. 2007;67(10):4783–9.CrossRefGoogle Scholar
  43. 43.
    Nagai T, et al. Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor β. Cancer Immunol Immunother. 2009;58(10):1577–86.CrossRefGoogle Scholar
  44. 44.
    Galmbacher K, et al. Shigella mediated depletion of macrophages in a murine breast cancer model is associated with tumor regression. PLoS ONE. 2010;5(3):e9572.CrossRefGoogle Scholar
  45. 45.
    Smahel M, Duskova M, Polakova I, Musil J. Enhancement of DNA vaccine potency against legumain. J Immunother. 2014;37(5):293–303.CrossRefGoogle Scholar
  46. 46.
    Roca H, Varsos ZS, Sud S, Craig MJ, Ying C, Pienta KJ. CCL2 and interleukin-6 promote survival of human CD11b + peripheral blood mononuclear cells and induce M2-type macrophage polarization. J Biol Chem. 2009;284(49):34342–54.CrossRefGoogle Scholar
  47. 47.
    Teng K-Y, et al. Blocking the CCL2-CCR2 axis using CCL2-neutralizing antibody is an effective therapy for hepatocellular cancer in a mouse model. Mol Cancer Ther. 2017;16(2):312–22.CrossRefGoogle Scholar
  48. 48.
    Qian B-Z, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature. 2011;475(7355):222–5.CrossRefGoogle Scholar
  49. 49.
    Brana I, et al. Carlumab, an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: an open-label, multicenter phase 1b study. Target Oncol. 2015;10(1):111–23.CrossRefGoogle Scholar
  50. 50.
    D’Incalci M, Zambelli A. Trabectedin for the treatment of breast cancer. Expert Opin Investig Drugs. 2016;25(1):105–15.CrossRefGoogle Scholar
  51. 51.
    Larsen AK, Galmarini CM, D’incalci M. Unique features of trabectedin mechanism of action. Cancer Chemother Pharmacol. 2016;77:663–71.CrossRefGoogle Scholar
  52. 52.
    Nywening TM, 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, non-randomised, phase 1b trial. Lancet Oncol. 2016;17(5):651–62.CrossRefGoogle Scholar
  53. 53.
    Zhang Q-Q, et al. CD11b deficiency suppresses intestinal tumor growth by reducing myeloid cell recruitment. Sci. Rep. 2015;5:15948.CrossRefGoogle Scholar
  54. 54.
    Ahn G-O, Tseng D, Liao C-H, Dorie MJ, Czechowicz A, Brown JM. Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc Natl Acad Sci USA. 2010;107(18):8363–8.CrossRefGoogle Scholar
  55. 55.
    Richardsen E, Uglehus RD, Johnsen SH, Busund L-T. Macrophage-colony stimulating factor (CSF1) predicts breast cancer progression and mortality. Anticancer Res. 2015;35(2):865–74.PubMedGoogle Scholar
  56. 56.
    Ao J-Y, et al. Colony-stimulating factor 1 receptor blockade inhibits tumor growth by altering the polarization of tumor-associated macrophages in hepatocellular carcinoma. Mol Cancer Ther. 2017;16(8):1544–54.CrossRefGoogle Scholar
  57. 57.
    Strachan DC, et al. CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells. Oncoimmunology. 2013;2(12):e26968.CrossRefGoogle Scholar
  58. 58.
    Ries CH, et al. Cancer cell targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell. 2014;25:846–59.CrossRefGoogle Scholar
  59. 59.
    Zhu Y, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74(18):5057–69.CrossRefGoogle Scholar
  60. 60.
    Weizman N, et al. Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. Oncogene. 2014;33(29):3812–9.CrossRefGoogle Scholar
  61. 61.
    Baer C, et al. Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity. Nat Cell Biol. 2016;18(7):790–802.CrossRefGoogle Scholar
  62. 62.
    Zhang L, Alizadeh D, Van Handel M, Kortylewski M, Yu H, Badie B. Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice. Glia. 2009;57(13):1458–67.CrossRefGoogle Scholar
  63. 63.
    Zhou J, et al. Myeloid STAT3 promotes lung tumorigenesis by transforming tumor immunosurveillance into tumor-promoting inflammation. Cancer Immunol Res. 2017;5(3):257–68.CrossRefGoogle Scholar
  64. 64.
    Edwards JP, Emens LA. The multikinase inhibitor Sorafenib reverses the suppression of IL-12 and enhancement of IL-10 by PGE2 in murine macrophages. Int Immunopharmacol. 2010;10(10):1220–8.CrossRefGoogle Scholar
  65. 65.
    Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–69. Scholar
  66. 66.
    Shiri S, et al. Dendrosomal curcumin suppresses metastatic breast cancer in mice by changing m1/m2 macrophage balance in the tumor microenvironment. Asian Pac J Cancer Prev. 2015;16(9):3917–22.CrossRefGoogle Scholar
  67. 67.
    Dong R, et al. The involvement of M2 macrophage polarization inhibition in fenretinide-mediated chemopreventive effects on colon cancer. Cancer Lett. 2017;388:43–53.CrossRefGoogle Scholar
  68. 68.
    Sakurai M, Nishio M, Yamamoto K, Okuda T, Kawano K, Ohnuki T. TMC-264, a novel inhibitor of STAT6 activation produced by Phoma sp. TC 1674. J Antibiot (Tokyo). 2003;56(6):513–9.CrossRefGoogle Scholar
  69. 69.
    Chiba Y, Todoroki M, Nishida Y, Tanabe M, Misawa M. A novel STAT6 inhibitor AS1517499 ameliorates antigen-induced bronchial hypercontractility in mice. Am J Respir Cell Mol Biol. 2009;41(5):516–24.CrossRefGoogle Scholar
  70. 70.
    Meyer I, Martinet W, Schrijvers DM, Timmermans J-P, Bult H, Meyer GRY. Toll-like receptor 7 stimulation by imiquimod induces macrophage autophagy and inflammation in atherosclerotic plaques. Basic Res Cardiol. 2012;107(3):269.CrossRefGoogle Scholar
  71. 71.
    Dewan MZ, et al. Synergy of topical toll-like receptor 7 agonist with radiation and low-dose cyclophosphamide in a mouse model of cutaneous breast cancer. Clin Cancer Res. 2012;18(24):6668–78.CrossRefGoogle Scholar
  72. 72.
    Zippelius A, Schreiner J, Herzig P, Müller P. Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment. Cancer Immunol Res. 2015;3(3):236–44.CrossRefGoogle Scholar
  73. 73.
    Weiss JM, et al. Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy. J Exp Med. 2010;207(11):2455–67.CrossRefGoogle Scholar
  74. 74.
    Vonderheide RH, et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol. 2007;25(7):876–83.CrossRefGoogle Scholar
  75. 75.
    Hemmi H, et al. A toll-like receptor recognizes bacterial DNA. Nature. 2000;408(6813):740–5.CrossRefGoogle Scholar
  76. 76.
    Shi Y, Felder MAR, Sondel PM, Rakhmilevich AL, Carbone PP. Synergy of anti-CD40, CpG and MPL in activation of mouse macrophages HHS public access. Mol Immunol. 2015;66(2):208–15.CrossRefGoogle Scholar
  77. 77.
    Georgoudaki A-M, et al. Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis. Cell Rep. 2016;15(9):2000–11.CrossRefGoogle Scholar
  78. 78.
    Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 2006;6(11):836–48.CrossRefGoogle Scholar
  79. 79.
    Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-γ: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75(2):163–89.CrossRefGoogle Scholar
  80. 80.
    Pujade-Lauraine E, et al. Intraperitoneal recombinant interferon gamma in ovarian cancer patients with residual disease at second-look laparotomy. J Clin Oncol. 1996;14(2):343–50.CrossRefGoogle Scholar
  81. 81.
    Giannopoulos A, et al. The immunomodulating effect of interferon-gamma intravesical instillations in preventing bladder cancer recurrence. Clin Cancer Res. 2003;9(15):5550–8.PubMedGoogle Scholar
  82. 82.
    Kane A, Yang I. Interferon-gamma in brain tumor immunotherapy. Neurosurg Clin N Am. 2010;21(1):77–86.CrossRefGoogle Scholar
  83. 83.
    Wallace A, et al. The vascular disrupting agent, DMXAA, directly activates dendritic cells through a MyD88-independent mechanism and generates antitumor cytotoxic T lymphocytes. Cancer Res. 2007;67(14):7011–9.CrossRefGoogle Scholar
  84. 84.
    Jassar AS, et al. Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8 + T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma. Cancer Res. 2005;65(24):11752–61.CrossRefGoogle Scholar
  85. 85.
    Daei Farshchi Adli A, Jahanban-Esfahlan R, Seidi K, Samandari-Rad S, Zarghami N. An overview on Vadimezan (DMXAA): the vascular disrupting agent. Chem Biol Drug Des. 2018;91(5):996–1006.CrossRefGoogle Scholar
  86. 86.
    Ding L, et al. Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages. Oncotarget. 2015;6(34):36441–55.CrossRefGoogle Scholar
  87. 87.
    Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2014;15(1):25–41.CrossRefGoogle Scholar
  88. 88.
    Kamat AM, et al. Definitions, end points, and clinical trial designs for non–muscle-invasive bladder cancer: recommendations from the international Bladder Cancer Group. J Clin Oncol. 2016;34(16):1935–44.CrossRefGoogle Scholar
  89. 89.
    Weijers Y, Arentsen HC, Arends TJH, Witjes JA. Management of low-risk and intermediate-risk non-muscle-invasive bladder carcinoma. Hematol Oncol Clin N Am. 2015;29(2):219–25.CrossRefGoogle Scholar
  90. 90.
    Biot C, et al. Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. Sci Transl Med. 2012;4(137ra72):137ra72.PubMedGoogle Scholar
  91. 91.
    Luo Y, Yamada H, Evanoff DP, Chen X. Role of Th1-stimulating cytokines in bacillus Calmette–Guerin (BCG)-induced macrophage cytotoxicity against mouse bladder cancer MBT-2 cells. Clin Exp Immunol. 2006;146(1):181–8.CrossRefGoogle Scholar
  92. 92.
    Takayama H, et al. Increased infiltration of tumor associated macrophages is associated with poor prognosis of bladder carcinoma in situ after intravesical bacillus Calmette-Guerin instillation. J Urol. 2009;181(4):1894–900.CrossRefGoogle Scholar
  93. 93.
    Martínez VG, Rubio C, Martínez-Fernández M, Segovia C, López-Calderón F, Garín MI, Teijeira A, Munera-Maravilla E, Varas A, Sacedón R, Guerrero F, Villacampa F, de la Rosa F, Castellano D, López-Collazo E, Paramio JM, Vicente Á, Dueñas M. BMP4 Induces M2 Macrophage Polarization and Favors Tumor Progression in Bladder Cancer. Clin Cancer Res. 2017;23(23):7388–99. Scholar
  94. 94.
    Sjödahl G, Lövgren K, Lauss M, Chebil G, Patschan O, Gudjonsson S, Månsson W, Fernö M, Leandersson K, Lindgren D, Liedberg F, Höglund M. Infiltration of CD3+ and CD68+ cells in bladder cancer is subtype specific and affects the outcome of patients with muscle-invasive tumors. Urol Oncol. 2014;32(6):791–7. Scholar
  95. 95.
    von der Maase H, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23(21):4602–8.CrossRefGoogle Scholar
  96. 96.
    Fu H, et al. Identification and validation of stromal immunotype predict survival and benefit from adjuvant chemotherapy in patients with muscle-invasive bladder cancer. Clin Cancer Res. 2018;24(13):3069–78.CrossRefGoogle Scholar
  97. 97.
    Takeuchi H, Tanaka M, Tanaka A, Tsunemi A, Yamamoto H. Predominance of M2-polarized macrophages in bladder cancer affects angiogenesis, tumor grade and invasiveness. Oncol Lett. 2016;11(5):3403–8.CrossRefGoogle Scholar
  98. 98.
    Bellmunt J, Powles T, Vogelzang NJ. A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: the future is now. Cancer Treat Rev. 2017;54:58–67.CrossRefGoogle Scholar
  99. 99.
    Lima L, et al. The predominance of M2-polarized macrophages in the stroma of low-hypoxic bladder tumors is associated with BCG immunotherapy failure. Urol Oncol. 2014;32(4):449–57.CrossRefGoogle Scholar
  100. 100.
    Shore ND, et al. Intravesical rAd-IFNα/Syn3 for patients with high-grade, bacillus calmette-guerin-refractory or relapsed non-muscle-invasive bladder cancer: a phase ii randomized study. J Clin Oncol. 2017;35(30):3410–6.CrossRefGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2018

Authors and Affiliations

  1. 1.Biomedical Research Institute I + 12University Hospital “12 de Octubre”MadridSpain
  2. 2.Molecular Oncology UnitCIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas)MadridSpain
  3. 3.Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)MadridSpain

Personalised recommendations