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The multifaceted immune regulation of bladder cancer

Abstract

Bladder cancer is an important public health concern owing to its prevalence, high recurrence risk and treatment failures. Maintaining the equilibrium between prompt and effective immunity and an excessive and protracted immune response is critical for successful immune defence. This delicate balance is ensured by intrinsic or extrinsic immunoregulatory mechanisms. Intrinsic control of immune cell activation is mediated by stimulatory and inhibitory receptors expressed on the effector cell itself, whereas extrinsic control is mediated via other immune cells by cell–cell contact and/or secretion of inhibitory factors. Tumours can exacerbate these immunosuppressive pathways, fostering a tolerant microenvironment. These mechanisms have previously been poorly described in urothelial carcinoma, but a growing body of evidence highlights the key role of immune regulation in bladder cancer. This process includes immune checkpoints (mostly programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1)), as well as regulatory T cells, myeloid-derived suppressor cells, tumour-associated macrophages and type 2 innate and adaptive lymphocytes. For each component, quantitative and qualitative alterations, clinical relevance and potential targeting strategies are currently being explored. An improved understanding of immune regulation pathways in bladder cancer development, recurrence and progression will help in the design of novel diagnostic and prognostic tools as well as treatments.

Key points

  • Immune regulatory mechanisms can be divided into intrinsic and extrinsic pathways, which include inhibitory and stimulatory receptors and regulatory cells, respectively.

  • The programmed cell death 1 (PD-1)–programmed cell death 1 ligand 1 (PD-L1) pathway is involved in bladder cancer immune regulation, and PD-L1 blockade results in impressive outcomes in patients with advanced disease; ongoing clinical trials are testing the effect of combined bacillus Calmette–Guérin (BCG) and anti-PD-L1 treatment.

  • The utility of inhibitory receptors (mostly PD-L1) as prognostic markers has proven difficult owing to conflicting results, highlighting the need to define standardized measurement methods.

  • Regulatory T cells and myeloid-derived suppressor cells (MDSCs) are key regulators of anti-tumour responses in bladder cancer, and type 2 immunity (TH2 cells and ILC2s) seems to also have an important function, especially in BCG therapy.

  • Future investigation of regulatory pathways involved in bladder tumour development and/or treatment failure will hopefully lead to the design of new immunotherapeutic strategies and predictors of clinical outcomes.

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Fig. 1: Network of immunoregulatory pathways in bladder cancer.
Fig. 2: T cell-mediated immune regulation in bladder cancer.
Fig. 3: Therapeutic agents targeting immunoregulatory mechanisms in bladder cancer.
Fig. 4: Macrophages, dendritic cells and mast cells in bladder cancer.
Fig. 5: MDSC-mediated immune regulation in bladder cancer.

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References

  1. Ehrlich, P. Über den jetzigen Stand der Karzinomforschung. Ned. Tijdschr. Geneeskd. 53, 273–290 (1909).

    Google Scholar 

  2. Kim, R., Emi, M. & Tanabe, K. Cancer immunoediting from immune surveillance to immune escape. Immunology 121, 1–14 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Burnet, M. Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications. Br. Med. J. 1, 841–847 (1957).

    CAS  PubMed  Google Scholar 

  4. Burnet, M. Cancer; a biological approach. I. The processes of control. Br. Med. J. 1, 779–786 (1957).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Thomas, L. On immunosurveillance in human cancer. Yale J. Biol. Med. 55, 329–333 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Dunn, G. P., Old, L. J. & Schreiber, R. D. The three Es of cancer immunoediting. Annu. Rev. Immunol. 22, 329–360 (2004).

    CAS  PubMed  Google Scholar 

  7. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. Fridman, W. H., Zitvogel, L., Sautes-Fridman, C. & Kroemer, G. The immune contexture in cancer prognosis and treatment. Nat. Rev. Clin. Oncol. 14, 717–734 (2017).

    Article  CAS  PubMed  Google Scholar 

  10. Becht, E. et al. Immune contexture, immunoscore, and malignant cell molecular subgroups for prognostic and theranostic classifications of cancers. Adv. Immunol. 130, 95–190 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Antoni, S. et al. Bladder cancer incidence and mortality: a global overview and recent trends. Eur. Urol. 71, 96–108 (2017).

    Article  PubMed  Google Scholar 

  12. Kamat, A. M. et al. Bladder cancer. Lancet 388, 2796–2810 (2016).

    Article  PubMed  Google Scholar 

  13. Babjuk, M. et al. EAU Guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur. Urol. 71, 447–461 (2017).

    Article  PubMed  Google Scholar 

  14. Alfred Witjes, J. et al. Updated 2016 EAU Guidelines on muscle-invasive and metastatic bladder cancer. Eur. Urol. 71, 462–475 (2017).

    Article  CAS  PubMed  Google Scholar 

  15. Stein, J. P. et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J. Clin. Oncol. 19, 666–675 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Fuertes Marraco, S. A., Neubert, N. J., Verdeil, G. & Speiser, D. E. Inhibitory receptors beyond T cell exhaustion. Front. Immunol. 6, 310 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Zhang, Q. & Vignali, D. A. Co-stimulatory and co-inhibitory pathways in autoimmunity. Immunology 44, 1034–1051 (2016).

    CAS  Google Scholar 

  18. Rabinovich, G. A., Gabrilovich, D. & Sotomayor, E. M. Immunosuppressive strategies that are mediated by tumor cells. Annu. Rev. Immunol. 25, 267–296 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mohme, M., Riethdorf, S. & Pantel, K. Circulating and disseminated tumour cells - mechanisms of immune surveillance and escape. Nat. Rev. Clin. Oncol. 14, 155–167 (2017).

    Article  CAS  PubMed  Google Scholar 

  20. Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Odorizzi, P. M. & Wherry, E. J. Inhibitory receptors on lymphocytes: insights from infections. J. Immunol. 188, 2957–2965 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Benson, D. M., Jr. et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 116, 2286–2294 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sun, C., Mezzadra, R. & Schumacher, T. N. Regulation and function of the PD-L1 checkpoint. Immunology 48, 434–452 (2018).

    CAS  Google Scholar 

  24. Buchbinder, E. & Hodi, F. S. Cytotoxic T lymphocyte antigen-4 and immune checkpoint blockade. J. Clin. Invest. 125, 3377–3383 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Egen, J. G., Kuhns, M. S. & Allison, J. P. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat. Immunol. 3, 611–618 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunology 27, 670–684 (2007).

    CAS  Google Scholar 

  27. Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Wherry, E. J. T cell exhaustion. Nat. Immunol. 12, 492–499 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Ahmadzadeh, M. et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114, 1537–1544 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pauken, K. E. & Wherry, E. J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 36, 265–276 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chevalier, M. F. et al. Immunoregulation of dendritic cell subsets by inhibitory receptors in urothelial cancer. Eur. Urol. 71, 854–857 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Krempski, J. et al. Tumor-infiltrating programmed death receptor-1+ dendritic cells mediate immune suppression in ovarian cancer. J. Immunol. 186, 6905–6913 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Lim, T. S. et al. PD-1 expression on dendritic cells suppresses CD8(+) T cell function and antitumor immunity. Oncoimmunology 5, e1085146 (2016).

    Article  PubMed  CAS  Google Scholar 

  34. Le Goux, C. et al. Correlation between messenger RNA expression and protein expression of immune checkpoint-associated molecules in bladder urothelial carcinoma: a retrospective study. Urol. Oncol. 35, 257–263 (2017).

    Article  PubMed  CAS  Google Scholar 

  35. Nakanishi, J. et al. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol. Immunother. 56, 1173–1182 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Huang, Y. et al. The prognostic significance of PD-L1 in bladder cancer. Oncol. Rep. 33, 3075–3084 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Inman, B. A. et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer 109, 1499–1505 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Wang, B. et al. Programmed death ligand-1 is associated with tumor infiltrating lymphocytes and poorer survival in urothelial cell carcinoma of the bladder. Cancer Sci. 110, 489–498 (2018).

  39. Wong, Y. N. S. et al. Urine-derived lymphocytes as a non-invasive measure of the bladder tumor immune microenvironment. J. Exp. Med. 215, 2748–2759 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Breyer, J. et al. High PDL1 mRNA expression predicts better survival of stage pT1 non-muscle-invasive bladder cancer (NMIBC) patients. Cancer Immunol. Immunother. 67, 403–412 (2018).

    Article  CAS  PubMed  Google Scholar 

  41. Bellmunt, J. et al. Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma. Ann. Oncol. 26, 812–817 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Rouanne, M. et al. Development of immunotherapy in bladder cancer: present and future on targeting PD(L)1 and CTLA-4 pathways. World J. Urol. 36, 1727–1740 (2018).

    Article  CAS  PubMed  Google Scholar 

  43. Bellmunt, J. et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N. Engl. J. Med. 376, 1015–1026 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Powles, T. et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 391, 748–757 (2018).

    Article  CAS  PubMed  Google Scholar 

  45. Massari, F. & Di Nunno, V. Atezolizumab for platinum-treated metastatic urothelial carcinoma. Lancet 391, 716–718 (2018).

    Article  PubMed  Google Scholar 

  46. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02807636 (2019).

  47. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02853305 (2018).

  48. Liakou, C. I. et al. CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc. Natl Acad. Sci. USA 105, 14987–14992 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Carthon, B. C. et al. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin. Cancer Res. 16, 2861–2871 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. van Hooren, L. et al. Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer. Eur J. Immunol. 47, 385–393 (2017).

    Article  PubMed  CAS  Google Scholar 

  51. Hahn, N. M. et al. Role of checkpoint inhibition in localized bladder cancer. Eur. Urol. Oncol. 1, 190–198 (2018).

    Google Scholar 

  52. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01928394 (2019).

  53. Sharma, P. et al. Nivolumab alone and with ipilimumab in previously treated metastatic urothelial carcinoma: checkmate 032 nivolumab 1 mg/kg plus ipilimumab 3 mg/kg expansion cohort results. J. Clin. Oncol. 37, 1608–1616 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Wang, Y. et al. Bacillus Calmette-Guerin and anti-PD-L1 combination therapy boosts immune response against bladder cancer. Onco. Targets Ther. 11, 2891–2899 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Chevalier, M. F. et al. Conventional and pd-l1-expressing regulatory T cells are enriched during BCG therapy and may limit its efficacy. Eur. Urol. 74, 540–544 (2018).

    Article  CAS  PubMed  Google Scholar 

  56. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02792192 (2019).

  57. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03519256 (2019).

  58. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02808143 (2019).

  59. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT02324582 (2018).

  60. Ghasemzadeh, A., Bivalacqua, T. J., Hahn, N. M. & Drake, C. G. New strategies in bladder cancer: a second coming for immunotherapy. Clin. Cancer Res. 22, 793–801 (2016).

    Article  CAS  PubMed  Google Scholar 

  61. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01968109 (2019).

  62. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02528357 (2019).

  63. Zibelman, M., Ramamurthy, C. & Plimack, E. R. Emerging role of immunotherapy in urothelial carcinoma-advanced disease. Urol. Oncol. 34, 538–547 (2016).

    Article  CAS  PubMed  Google Scholar 

  64. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01391143 (2019).

  65. Bellmunt, J., Powles, T. & Vogelzang, N. J. A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now. Cancer Treat. Rev. 54, 58–67 (2017).

    Article  CAS  PubMed  Google Scholar 

  66. Loskog, A. et al. Human bladder carcinoma is dominated by T-regulatory cells and Th1 inhibitory cytokines. J. Urol. 177, 353–358 (2007).

    Article  PubMed  Google Scholar 

  67. Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6, 295–307 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).

    CAS  PubMed  Google Scholar 

  69. Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Miyara, M. & Sakaguchi, S. Human FoxP3(+)CD4(+) regulatory T cells: their knowns and unknowns. Immunol. Cell Biol. 89, 346–351 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. Vignali, D. A., Collison, L. W. & Workman, C. J. How regulatory T cells work. Nat. Rev. Immunol. 8, 523–532 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Woo, E. Y. et al. Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 61, 4766–4772 (2001).

    CAS  PubMed  Google Scholar 

  73. Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942–949 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Tanaka, A. & Sakaguchi, S. Regulatory T cells in cancer immunotherapy. Cell Res. 27, 109–118 (2017).

    Article  CAS  PubMed  Google Scholar 

  75. Salama, P. et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J. Clin. Oncol. 27, 186–192 (2009).

    Article  PubMed  Google Scholar 

  76. Tsai, Y. S. et al. Loss of nuclear prothymosin-alpha expression is associated with disease progression in human superficial bladder cancer. Virchows Arch. 464, 717–724 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Horn, T. et al. The prognostic effect of tumour-infiltrating lymphocytic subpopulations in bladder cancer. World J. Urol. 34, 181–187 (2016).

    Article  CAS  PubMed  Google Scholar 

  78. Parodi, A. et al. Residual tumor micro-foci and overwhelming regulatory T lymphocyte infiltration are the causes of bladder cancer recurrence. Oncotarget 7, 6424–6435 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Baras, A. S. et al. The ratio of CD8 to Treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive urothelial carcinoma of the bladder. Oncoimmunology 5, e1134412 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Miyake, M. et al. Regulatory T cells and tumor-associated macrophages in the tumor microenvironment in non-muscle invasive bladder cancer treated with intravesical bacille Calmette-Guerin: a long-term follow-up study of a Japanese cohort. Int. J. Mol. Sci. 18, E2186 (2017).

  81. Liu, Y. N. et al. Sphingosine 1 phosphate receptor-1 (S1P1) promotes tumor-associated regulatory T cell expansion: leading to poor survival in bladder cancer. Cell Death Dis. 10, 50 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Winerdal, M. E. et al. FOXP3 and survival in urinary bladder cancer. BJU Int. 108, 1672–1678 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Winerdal, M. E. et al. Urinary bladder cancer Tregs suppress MMP2 and potentially regulate invasiveness. Cancer Immunol. Res. 6, 528–538 (2018).

    Article  CAS  PubMed  Google Scholar 

  84. Krantz, D. et al. Neoadjuvant chemotherapy reinforces antitumour T cell response in urothelial urinary bladder cancer. Eur. Urol. 74, 688–692 (2018).

    Article  CAS  PubMed  Google Scholar 

  85. Arce Vargas, F. et al. Fc-Optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors. Immunology 46, 577–586 (2017).

    CAS  Google Scholar 

  86. Qureshi, O. S. et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600–603 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Marabelle, A. et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J. Clin. Invest. 123, 2447–2463 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Romano, E. et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc. Natl Acad. Sci. USA 112, 6140–6145 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Simpson, T. R. et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695–1710 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zappasodi, R. et al. Rational design of anti-GITR-based combination immunotherapy. Nat. Med. 25, 759–766 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02628574 (2019).

  92. Ohue, Y. & Nishikawa, H. Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target? Cancer Sci. 110, 2080–2089 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sugiyama, D. et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc. Natl Acad. Sci. USA 110, 17945–17950 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Maeda, S., Murakami, K., Inoue, A., Yonezawa, T. & Matsuki, N. CCR4 Blockade depletes regulatory T cells and prolongs survival in a canine model of bladder cancer. Cancer Immunol. Res. 7, 1175–1187 (2019).

    Article  PubMed  Google Scholar 

  95. Veglia, F., Perego, M. & Gabrilovich, D. Myeloid-derived suppressor cells coming of age. Nat. Immunol. 19, 108–119 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ugel, S., De Sanctis, F., Mandruzzato, S. & Bronte, V. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J. Clin. Invest. 125, 3365–3376 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Sica, A., Porta, C., Amadori, A. & Pasto, A. Tumor-associated myeloid cells as guiding forces of cancer cell stemness. Cancer Immunol. Immunother. 66, 1025–1036 (2017).

    Article  CAS  PubMed  Google Scholar 

  98. Solito, S. et al. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann. N. Y. Acad. Sci. 1319, 47–65 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Yuan, X. K., Zhao, X. K., Xia, Y. C., Zhu, X. & Xiao, P. Increased circulating immunosuppressive CD14(+)HLA-DR(-/low) cells correlate with clinical cancer stage and pathological grade in patients with bladder carcinoma. J. Int. Med. Res. 39, 1381–1391 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Yang, G. et al. Accumulation of myeloid-derived suppressor cells (MDSCs) induced by low levels of IL-6 correlates with poor prognosis in bladder cancer. Oncotarget 8, 38378–38388 (2017).

    PubMed  PubMed Central  Google Scholar 

  101. Eruslanov, E. et al. Circulating and tumor-infiltrating myeloid cell subsets in patients with bladder cancer. Int J. Cancer 130, 1109–1119 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Brandau, S. et al. Myeloid-derived suppressor cells in the peripheral blood of cancer patients contain a subset of immature neutrophils with impaired migratory properties. J. Leukoc. Biol. 89, 311–317 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Zhang, H. et al. CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer. Oncogene 36, 2095–2104 (2017).

    Article  CAS  PubMed  Google Scholar 

  104. Chevalier, M. F. et al. ILC2-modulated T cell-to-MDSC balance is associated with bladder cancer recurrence. J. Clin. Invest. 127, 2916–2929 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  105. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02735512 (2019).

  106. Serafini, P. et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J. Exp. Med. 203, 2691–2702 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Fleming, V. et al. Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression. Front. Immunol. 9, 398 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Yu, H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9, 798–809 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. He, W. et al. Re-polarizing myeloid-derived suppressor cells (MDSCs) with cationic polymers for cancer immunotherapy. Sci. Rep. 6, 24506 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kodumudi, K. N. et al. A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin. Cancer Res. 16, 4583–4594 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Eruslanov, E., Daurkin, I., Vieweg, J., Daaka, Y. & Kusmartsev, S. Aberrant PGE(2) metabolism in bladder tumor microenvironment promotes immunosuppressive phenotype of tumor-infiltrating myeloid cells. Int. Immunopharmacol. 11, 848–855 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mirza, N. et al. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res. 66, 9299–9307 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Kusmartsev, S. et al. Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma. Clin. Cancer Res. 14, 8270–8278 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Nefedova, Y. et al. Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res. 67, 11021–11028 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02403778 (2018).

  116. Chalmin, F. et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J. Clin. Invest. 120, 457–471 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Obermajer, N., Muthuswamy, R., Odunsi, K., Edwards, R. P. & Kalinski, P. PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res. 71, 7463–7470 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Umansky, V., Blattner, C., Gebhardt, C. & Utikal, J. CCR5 in recruitment and activation of myeloid-derived suppressor cells in melanoma. Cancer Immunol. Immunother. 66, 1015–1023 (2017).

    Article  CAS  PubMed  Google Scholar 

  119. Halama, N. et al. Tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by anti-ccr5 therapy in cancer patients. Cancer Cell 29, 587–601 (2016).

    Article  CAS  PubMed  Google Scholar 

  120. Weber, J. et al. Phase I/II Study of metastatic melanoma patients treated with nivolumab who had progressed after ipilimumab. Cancer Immunol. Res. 4, 345–353 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Meyer, C. et al. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol. Immunother. 63, 247–257 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03302247 (2019).

  123. Chen, H. M. et al. Myeloid-derived suppressor cells as an immune parameter in patients with concurrent sunitinib and stereotactic body radiotherapy. Clin. Cancer Res. 21, 4073–4085 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Ko, J. S. et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin. Cancer Res. 15, 2148–2157 (2009).

    CAS  PubMed  Google Scholar 

  125. Tavazoie, M. F. et al. LXR/ApoE Activation restricts innate immune suppression in. Cancer. Cell 172, 825–840 (2018).

    CAS  Google Scholar 

  126. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02922764 (2019).

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

    Article  CAS  PubMed  Google Scholar 

  128. Zhang, Q. W. et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLOS ONE 7, e50946 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Heusinkveld, M. & van der Burg, S. H. Identification and manipulation of tumor associated macrophages in human cancers. J. Transl. Med. 9, 216 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Wang, B. et al. High CD204+ tumor-infiltrating macrophage density predicts a poor prognosis in patients with urothelial cell carcinoma of the bladder. Oncotarget 6, 20204–20214 (2015).

    PubMed  PubMed Central  Google Scholar 

  131. 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. 11, 3403–3408 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Hanada, T. et al. Prognostic value of tumor-associated macrophage count in human bladder cancer. Int. J. Urol. 7, 263–269 (2000).

    Article  CAS  PubMed  Google Scholar 

  133. Sjodahl, G. et al. Infiltration of CD3(+) and CD68(+) cells in bladder cancer is subtype specific and affects the outcome of patients with muscle-invasive tumors. Urol. Oncol. 32, 791–797 (2014).

    Article  PubMed  Google Scholar 

  134. Ayari, C. et al. Bladder tumor infiltrating mature dendritic cells and macrophages as predictors of response to bacillus Calmette-Guerin immunotherapy. Eur. Urol. 55, 1386–1395 (2009).

    Article  CAS  PubMed  Google Scholar 

  135. Ajili, F., Kourda, N., Darouiche, A., Chebil, M. & Boubaker, S. Prognostic value of tumor-associated macrophages count in human non-muscle-invasive bladder cancer treated by BCG immunotherapy. Ultrastruct. Pathol. 37, 56–61 (2013).

    Article  PubMed  Google Scholar 

  136. 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. 32, 449–457 (2014).

    Article  CAS  PubMed  Google Scholar 

  137. Suriano, F. et al. Tumor associated macrophages polarization dictates the efficacy of BCG instillation in non-muscle invasive urothelial bladder cancer. J. Exp. Clin. Cancer Res. 32, 87 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  138. 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. 181, 1894–1900 (2009).

    Article  CAS  PubMed  Google Scholar 

  139. Dufresne, M. et al. Pro-inflammatory type-1 and anti-inflammatory type-2 macrophages differentially modulate cell survival and invasion of human bladder carcinoma T24 cells. Mol. Immunol. 48, 1556–1567 (2011).

    Article  CAS  PubMed  Google Scholar 

  140. Asano, T. et al. CD169-positive sinus macrophages in the lymph nodes determine bladder cancer prognosis. Cancer Sci. 109, 1723–1730 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ries, C. H. et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25, 846–859 (2014).

    Article  CAS  PubMed  Google Scholar 

  142. Johansson, M., Denardo, D. G. & Coussens, L. M. Polarized immune responses differentially regulate cancer development. Immunol. Rev. 222, 145–154 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Disis, M. L. Immune regulation of cancer. J. Clin. Oncol. 28, 4531–4538 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Bohner, P. et al. Double positive cd4(+)cd8(+) T cells are enriched in urological cancers and favor T helper-2 polarization. Front. Immunol. 10, 622 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Agarwal, A. et al. Flow cytometric analysis of Th1 and Th2 cytokines in PBMCs as a parameter of immunological dysfunction in patients of superficial transitional cell carcinoma of bladder. Cancer Immunol. Immunother. 55, 734–743 (2006).

    Article  CAS  PubMed  Google Scholar 

  146. Satyam, A., Singh, P., Badjatia, N., Seth, A. & Sharma, A. A disproportion of TH1/TH2 cytokines with predominance of TH2, in urothelial carcinoma of bladder. Urol. Oncol. 29, 58–65 (2011).

    Article  CAS  PubMed  Google Scholar 

  147. Lang, F., Linlin, M., Ye, T. & Yuhai, Z. Alterations of dendritic cell subsets and TH1/TH2 cytokines in the peripheral circulation of patients with superficial transitional cell carcinoma of the bladder. J. Clin. Lab. Anal. 26, 365–371 (2012).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  148. Efstathiou, J. A. et al. Impact of immune and stromal infiltration on outcomes following bladder-sparing trimodality therapy for muscle-invasive bladder cancer. Eur. Urol. 76, 59–68 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Kanhere, A. et al. T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nat. Commun. 3, 1268 (2012).

    Article  PubMed  CAS  Google Scholar 

  150. Bahria-Sediki, I. B. et al. Clinical significance of T-bet, GATA-3, and Bcl-6 transcription factor expression in bladder carcinoma. J. Transl Med. 14, 144 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Inoue, S. et al. GATA3 immunohistochemistry in urothelial carcinoma of the upper urinary tract as a urothelial marker and a prognosticator. Hum. Pathol. 64, 83–90 (2017).

    Article  CAS  PubMed  Google Scholar 

  152. Li, Y. et al. Loss of GATA3 in bladder cancer promotes cell migration and invasion. Cancer Biol. Ther. 15, 428–435 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Agarwal, A., Agrawal, U., Verma, S., Mohanty, N. K. & Saxena, S. Serum Th1 and Th2 cytokine balance in patients of superficial transitional cell carcinoma of bladder pre- and post-intravesical combination immunotherapy. Immunopharmacol. Immunotoxicol. 32, 348–356 (2010).

    Article  CAS  PubMed  Google Scholar 

  154. Saint, F. et al. Prognostic value of a T helper 1 urinary cytokine response after intravesical bacillus Calmette-Guerin treatment for superficial bladder cancer. J. Urol. 167, 364–367 (2002).

    Article  PubMed  Google Scholar 

  155. Watanabe, E. et al. Urinary interleukin-2 may predict clinical outcome of intravesical bacillus Calmette-Guerin immunotherapy for carcinoma in situ of the bladder. Cancer Immunol. Immunother. 52, 481–486 (2003).

    Article  CAS  PubMed  Google Scholar 

  156. Pichler, R. et al. Intratumoral Th2 predisposition combines with an increased Th1 functional phenotype in clinical response to intravesical BCG in bladder cancer. Cancer Immunol. Immunother. 66, 427–440 (2017).

    Article  CAS  PubMed  Google Scholar 

  157. Redelman-Sidi, G., Glickman, M. S. & Bochner, B. H. The mechanism of action of BCG therapy for bladder cancer – a current perspective. Nat. Rev. Urol. 11, 153–162 (2014).

    Article  CAS  PubMed  Google Scholar 

  158. Saint, F. et al. Urinary IL-2 assay for monitoring intravesical bacillus Calmette-Guerin response of superficial bladder cancer during induction course and maintenance therapy. Int. J. Cancer 107, 434–440 (2003).

    Article  CAS  PubMed  Google Scholar 

  159. Pichler, R. et al. Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical bacillus calmette-guerin therapy in bladder cancer. Oncotarget 7, 39916–39930 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Luo, Y., Han, R., Evanoff, D. P. & Chen, X. Interleukin-10 inhibits Mycobacterium bovis bacillus Calmette-Guerin (BCG)-induced macrophage cytotoxicity against bladder cancer cells. Clin. Exp. Immunol. 160, 359–368 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Luo, Y., Yamada, H., Evanoff, D. P. & 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. 146, 181–188 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Saint, F. et al. Evaluation of cellular tumour rejection mechanisms in the peritumoral bladder wall after bacillus Calmette-Guerin treatment. BJU Int. 88, 602–610 (2001).

    Article  CAS  PubMed  Google Scholar 

  163. Bisiaux, A. et al. Molecular analyte profiling of the early events and tissue conditioning following intravesical bacillus calmette-guerin therapy in patients with superficial bladder cancer. J. Urol. 181, 1571–1580 (2009).

    Article  CAS  PubMed  Google Scholar 

  164. Luo, Y. & Knudson, M. J. Mycobacterium bovis bacillus Calmette-Guerin-induced macrophage cytotoxicity against bladder cancer cells. Clin. Dev. Immunol. 2010, 357591 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Bockholt, N. A. et al. Anti-interleukin-10R1 monoclonal antibody enhances bacillus Calmette-Guerin induced T-helper type 1 immune responses and antitumor immunity in a mouse orthotopic model of bladder cancer. J. Urol. 187, 2228–2235 (2012).

    Article  CAS  PubMed  Google Scholar 

  166. Luo, Y., Chen, X. & O'Donnell, M. A. Role of Th1 and Th2 cytokines in BCG-induced IFN-gamma production: cytokine promotion and simulation of BCG effect. Cytokine 21, 17–26 (2003).

    Article  CAS  PubMed  Google Scholar 

  167. Luo, Y. et al. Recombinant mycobacterium bovis bacillus calmette-guerin (BCG) expressing mouse IL-18 augments Th1 immunity and macrophage cytotoxicity. Clin. Exp. Immunol. 137, 24–34 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Thalmann, G. N. et al. Urinary interleukin-8 and 18 predict the response of superficial bladder cancer to intravesical therapy with bacillus Calmette-Guerin. J. Urol. 164, 2129–2133 (2000).

    Article  CAS  PubMed  Google Scholar 

  169. Rigoni, A., Colombo, M. P. & Pucillo, C. The role of mast cells in molding the tumor microenvironment. Cancer Microenviron. 8, 167–176 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. Liu, Z. et al. Tumor stroma-infiltrating mast cells predict prognosis and adjuvant chemotherapeutic benefits in patients with muscle invasive bladder cancer. Oncoimmunology 7 (2018).

  171. Tait Wojno, E. D. & Artis, D. Emerging concepts and future challenges in innate lymphoid cell biology. J. Exp. Med. 213, 2229–2248 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Bailey, S. R. et al. Th17 cells in cancer: the ultimate identity crisis. Front. Immunol. 5, 276 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Chiossone, L., Dumas, P. Y., Vienne, M. & Vivier, E. Natural killer cells and other innate lymphoid cells in cancer. Nat. Rev. Immunol. 18, 671–688 (2018).

    Article  CAS  PubMed  Google Scholar 

  174. Trabanelli, S. et al. Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis. Nat. Commun. 8, 593 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Bruce, D. W. et al. Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease. J. Clin. Invest. 127, 1813–1825 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  176. MalekZadeh, K., Nikbakht, M., Sadeghi, I. A., Singh, S. K. & Sobti, R. C. Overexpression of IL-13 in patients with bladder cancer. Cancer Invest. 28, 201–207 (2010).

    Article  CAS  PubMed  Google Scholar 

  177. Margel, D., Pevsner-Fischer, M., Baniel, J., Yossepowitch, O. & Cohen, I. R. Stress proteins and cytokines are urinary biomarkers for diagnosis and staging of bladder cancer. Eur. Urol. 59, 113–119 (2011).

    Article  CAS  PubMed  Google Scholar 

  178. Spencer, S. P. et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343, 432–437 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 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. 24, 3069–3078 (2018).

    Article  CAS  PubMed  Google Scholar 

  180. Routy, B. et al. The gut microbiota influences anticancer immunosurveillance and general health. Nat. Rev. Clin. Oncol. 15, 382–396 (2018).

    Article  CAS  PubMed  Google Scholar 

  181. Bucevic Popovic, V. et al. The urinary microbiome associated with bladder cancer. Sci. Rep. 8, 12157 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).

    Article  CAS  PubMed  Google Scholar 

  183. Sweis, R. F. et al. Molecular drivers of the non-t-cell-inflamed tumor microenvironment in urothelial bladder cancer. Cancer Immunol. Res. 4, 563–568 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Research in the Derré lab is supported by The Swiss Cancer League (# KFS-4101–02–2017).

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Schneider, A.K., Chevalier, M.F. & Derré, L. The multifaceted immune regulation of bladder cancer. Nat Rev Urol 16, 613–630 (2019). https://doi.org/10.1038/s41585-019-0226-y

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