Immunosuppressed Microenvironment – An Emerging Target in Prostate Cancer Management

European Oncology & Haematology, 2014;10(1):51–7

The Role of the Tumour Microenvironment in Prostate Cancer Development, Progression and Control
In order for a tumour to progress and develop into a life-threatening entity, it must develop certain attributes. These include the ability to move, to degrade tissue matrix, to survive in blood and to being able to establish itself in a new tissue environment. It obtains these attributes via signals from the microenvironment that turn on gene transcription.13 The transformation of proliferating stem cells and subsequent tumour invasion depends on complex interactions between cancer cells and a microenvironment of activated inflammatory cells and stromal cell elements.14 In addition to these components, the tumour microenvironment includes matrix-degrading enzymes, endothelial cells and fibroblasts15 as well as factors that stimulate angiogenesis.16 Fibroblasts are able to buffer the acidity generated in the hypoxic conditions of the microenvironment, allowing more cells to survive the low pH, therefore increasing tumour progression.17

At distal metastatic sites, immune cells and fibroblasts establish premetastatic niches, providing permissive environments for migrating tumour cells to colonise and establish metastasis. Primary and metastatic sites communicate through soluble mediators and exosomes both from primary tumour cells and from immune and stromal cells of the tumour microenvironment.18 In addition, a number of secreted proteins derived from the tumour microenvironment have been found to attenuate the effects of cytotoxic chemotherapy in vivo, promoting subsequent treatment resistance.19,20

In prostate cancer, the unexpected finding that earlier-stage prostate cancer may be more resistant to chemotherapy than CRPC21 has led to the suggestion that prostate cancer passes through a microenvironment dependent state and progresses to a microenvironment-independent state.22 Since chemotherapy predominantly affects tumour cells, this finding suggests that targeting tumour cells is insufficient to prevent prostate cancer progression and that prostate cancer therapies should target the tumour microenvironment. Unlike tumour cells, stromal cells within the tumour microenvironment are genetically stable and therefore represent an attractive therapeutic target with reduced risk of resistance and tumour recurrence.18 Chronic inflammation of the prostate also plays a major role in the development of prostate cancer. Epidemiological studies show that prostate cancer is more common in populations with higher levels of baseline inflammation.23 Inflammatory cytokines promote sustained activation of the transcription factor nuclear factor kappa B (NF-kB), which is correlated with metastatic progression to CRPC.24

Immunosuppressive Components of the Tumour Microenvironment
Inflammation leads to disruption of the immune response and regulation of the tumour microenvironment, although the mechanisms by which specific inflammatory mediators contribute to tumour progression are not fully understood.24 Therefore, recent research has focused on modulation of the immune components of the tumour microenvironment.

As tumours progress, a number of mechanisms are activated that enable them to evade immune surveillance.25,26 Myeloid cells, a heterogeneous population of cells derived from the bone marrow, are actively recruited to the tumour microenvironment.26 Two types of myeloid cells: myeloidderived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs) have been the focus of particular attention.26–29 The levels of MDSCs are greatly enhanced in humans during chronic pathological conditions such as infections, inflammation and cancer. MDSCs are immature myeloid cells that fail to complete their differentiation under chronic conditions typically encountered in the tumour microenvironment and lack the expression of mature myeloid cell surface makers.30 MDSCs inhibit innate and adaptive immunity, promoting tumour immune escape. This is achieved by numerous mechanisms including secretion of cytokines and upregulation of nitric oxide, production of reactive oxygen species (ROS), activation of L-arginase and sequestration of cystine, leading to T cell apoptosis, the nitration of chemokines and T cell receptors, blocking T cell migration and tumour cell killing and ultimately resulting in the inhibition of cytokine production that are crucial for T cell anti-tumour functions.27,29,31–34 MDSCs also impair immune cell function in the tumour microenvironment, an important step in tumour progression. MDSCs inhibit the activation of cells with cytotoxic anti-tumour activity and regulatory natural killer (NK)/NK T (NKT) cells,35,36 as well as modulating the de novo development of regulatory T cells (Tregs) 36

In addition to their immunosuppressive role, MDSCs can also directly stimulate tumour growth and expansion by stimulating pro-angiogenic cytokines and creating a favourable environment for metastasis (see Figure 1).29,30,37 MDSCs are actively recruited to the tumour microenvironment from the bloodstream, a process mediated by chemokines, integrins and adhesion factor molecules, which allows further accumulation of these cells in the tumour microenvironment.28 Hypoxia also stimulates the recruitment of circulating myeloid cells to tissues by promoting expression of genes associated with angiogenesis, metastasis and invasion, which is controlled by transcription factor complexes of hypoxia-inducible factors (HIFs).38

Levels of circulating MDSCs increase with age and are elevated in individuals in remission from cancer. This may be a result of age-related increased levels of inflammatory cytokines that facilitate the formation of MDSCs. Individuals in remission from cancer may continuously produce factors that promote the development of MDSCs.35 This raises a number of questions: do individuals with high levels of MDSCs have a microenvironment that supports tumour growth, and hence have increased risk of developing cancer? Do patients with a history of cancer undergo permanent changes in MDSC production? If so, could this contribute to an increased risk of developing seemingly unrelated cancers or other chronic inflammatory conditions? Larger studies are required to further explore these hypotheses.

The second important cellular components of the tumour microenvironment are TAMs, which have numerous roles in cancer progression (see Figure 2).28,39 In tumour microenvironments, TAMs are polarised towards the M2 phenotype, which affect diverse processes such as suppression of adaptive immunity, promoting angiogenesis, tumour cell proliferation and metastasis during tumour progression.40,41 By contrast, the ‘classically activated’ M1 phenotype promotes immune responses and inhibits angiogenesis, thus suppressing tumour development. The M2 TAMs secrete growth factors and cytokines, causing matrix remodelling, and suppression of the immune system’s ability to alert other immune cells to the presence of cancer cells.42 High levels of TAMs have been associated with poor prognosis in prostate cancer.43 MDSCs and TAMs therefore represent a promising target for therapeutic intervention. Strategies may include inhibition of recruitment to the tumour microenvironment, which may reduce resistance to chemotherapy,44 or partial reprogramming of TAM polarisation towards an M1-like phenotype.

  1. SEER, SEER Stat Fact Sheets: Prostate Cancer. Available at: (accessed 13 January 2014).
  2. Horwich A, Hugosson J, de Reijke T, et al., Prostate cancer: ESMO Consensus Conference Guidelines 2012, Ann Oncol, 2013;24:1141–62.
  3. Gravis G, Fizazi K, Joly F, et al., Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial, Lancet Oncol, 2013;14:149–58.
  4. Knudsen KE, Scher HI, Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer, Clin Cancer Res, 2009;15:4792–8.
  5. Kirby M, Hirst C, Crawford ED, Characterising the castrationresistant prostate cancer population: a systematic review, Int J Clin Pract, 2011;65:1180–92.
  6. Rathkopf DE, Smith MR, de Bono JS, et al., Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302), Eur Urol, 2014; [Epub ahead of print].
  7. El-Amm J, Aragon-Ching JB, The changing landscape in the treatment of metastatic castration-resistant prostate cancer, Ther Adv Med Oncol, 2013;5:25–40.
  8. van Soest RJ, van Royen ME, de Morree ES, et al., Crossresistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer, Eur J Cancer, 2013;49:3821–30.
  9. Loriot Y, Bianchini D, Ileana E, et al., Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100), Ann Oncol, 2013;24:1807–12.
  10. Noonan KL, North S, Bitting RL, et al., Clinical activity of abiraterone acetate in patients with metastatic castrationresistant prostate cancer progressing after enzalutamide, Ann Oncol, 2013;24:1802–7.
  11. Kantoff PW, Higano CS, Shore ND, et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer, N Engl J Med, 2010;363:411–22.
  12. Mendoza M, Khanna C, Revisiting the seed and soil in cancer metastasis, Int J Biochem Cell Biol, 2009;41:1452–62.
  13. Mbeunkui F, Johann DJ, Jr, Cancer and the tumor microenvironment: a review of an essential relationship, Cancer Chemother Pharmacol, 2009;63:571-82.
  14. O’Byrne KJ, Dalgleish AG, Chronic immune activation and inflammation as the cause of malignancy, Br J Cancer, 2001;85:473–83.
  15. Bhowmick NA, Neilson EG, Moses HL, Stromal fibroblasts in cancer initiation and progression, Nature, 2004;432:332–7.
  16. Weis SM, Cheresh DA, Tumor angiogenesis: molecular pathways and therapeutic targets, Nat Med, 2011;17:1359–70.
  17. Koukourakis MI, Giatromanolaki A, Harris AL, et al., Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma, Cancer Res, 2006;66:632–7.
  18. Quail DF, Joyce JA, Microenvironmental regulation of tumor progression and metastasis, Nat Med, 2013;19:1423–37.
  19. Sun Y, Campisi J, Higano C, et al., Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B, Nat Med, 2012;18:1359–68.
  20. Rosser C, Targeting prostatic tumor micro-environment to address therapy resistance, Transl Cancer Res, 2013;2:62–3.
  21. Millikan RE, Wen S, Pagliaro LC, et al., Phase III trial of androgen ablation with or without three cycles of systemic chemotherapy for advanced prostate cancer, J Clin Oncol, 2008;26:5936–42.
  22. Efstathiou E, Logothetis CJ, A new therapy paradigm for prostate cancer founded on clinical observations, Clin Cancer Res, 2010;16:1100–7.
  23. Schenk JM, Kristal AR, Neuhouser ML, et al., Biomarkers of systemic inflammation and risk of incident, symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial, Am J Epidemiol, 2010;171:571–82.
  24. Nguyen DP, Li J, Tewari AK, Inflammation and prostate cancer: the role of interleukin-6, BJU Int, 2014;113(6):986–92.
  25. Bhardwaj N, Harnessing the immune system to treat cancer, J Clin Invest, 2007;117:1130–6.
  26. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V, Coordinated regulation of myeloid cells by tumours, Nat Rev Immunol, 2012;12:253–68.
  27. Schmid MC, Varner JA, Myeloid cells in the tumor microenvironment: modulation of tumor angiogenesis and tumor inflammation, J Oncol, 2010;2010:201026.
  28. Schmid MC, Varner JA, Myeloid cells in tumor inflammation, Vasc Cell, 2012;4:14.
  29. Talmadge JE, Gabrilovich DI, History of myeloid-derived suppressor cells, Nat Rev Cancer, 2013;13:739–52.
  30. Umansky V, Sevko A, Tumor microenvironment and myeloid-derived suppressor cells, Cancer Microenviron, 2013;6:169–77.
  31. Kusmartsev S, Gabrilovich DI, Role of immature myeloid cells in mechanisms of immune evasion in cancer, Cancer Immunol Immunother, 2006;55:237–45.
  32. Gabrilovich DI, Nagaraj S, Myeloid-derived suppressor cells as regulators of the immune system, Nat Rev Immunol, 2009;9:162–74.
  33. Ostrand-Rosenberg S, Sinha P, Myeloid-derived suppressor cells: linking inflammation and cancer, J Immunol, 2009;182:4499–506.
  34. Ostrand-Rosenberg S, Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity, Cancer Immunol Immunother, 2010;59:1593–600.
  35. Bowdish DM, Myeloid-derived suppressor cells, age and cancer, Oncoimmunology, 2013;2:e24754.
  36. Lindau D, Gielen P, Kroesen M, et al., The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells, Immunology, 2013;138:105–15.
  37. Sevko A, Umansky V, Myeloid-derived suppressor cells interact with tumors in terms of myelopoiesis, tumorigenesis and immunosuppression: thick as thieves, J Cancer, 2013;4:3–11.
  38. Giaccia AJ, Simon MC, Johnson R, The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease, Genes Dev, 2004;18:2183–94.
  39. Monu NR, Frey AB, Myeloid-derived suppressor cells and anti-tumor T cells: a complex relationship, Immunol Invest, 2012;41:595–613.
  40. Shevach EM, The resurrection of T cell-mediated suppression, J Immunol, 2011;186:3805–7.
  41. Huen NY, Pang AL, Tucker JA, et al., Up-regulation of proliferative and migratory genes in regulatory T cells from patients with metastatic castration-resistant prostate cancer, Int J Cancer, 2013;133:373–82.
  42. Sica A, Larghi P, Mancino A, et al., Macrophage polarization in tumour progression, Semin Cancer Biol, 2008;18:349–55.
  43. Nonomura N, Takayama H, Nakayama M, et al., Infiltration of tumour-associated macrophages in prostate biopsy specimens is predictive of disease progression after hormonal therapy for prostate cancer, BJU Int, 2011;107:1918–22.
  44. Nakasone ES, Askautrud HA, Kees T, et al., Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance, Cancer Cell, 2012;21:488–503.
  45. Wilson J, Balkwill F, The role of cytokines in the epithelial cancer microenvironment, Semin Cancer Biol, 2002;12:113–20.
  46. Sparvero LJ, Asafu-Adjei D, Kang R, et al., RAGE (Receptor for Advanced Glycation Endproducts), RAGE ligands, and their role in cancer and inflammation, J Transl Med, 2009;7:17.
  47. Ridnour LA, Cheng RY, Switzer CH, et al., Molecular pathways: toll-like receptors in the tumor microenvironment – poor prognosis or new therapeutic opportunity, Clin Cancer Res, 2013;19:1340–6.
  48. Mai CW, Kang YB, Pichika MR, Should a toll-like receptor 4 (TLR-4) agonist or antagonist be designed to treat cancer? TLR-4: its expression and effects in the ten most common cancers, Onco Targets Ther, 2013;6:1573–87.
  49. Srikrishna G, S100A8 and S100A9: new insights into their roles in malignancy, J Innate Immun, 2012;4:31–40.
  50. Ghavami S, Chitayat S, Hashemi M, et al., S100A8/A9: a Janus-faced molecule in cancer therapy and tumorgenesis, Eur J Pharmacol, 2009;625:73–83.
  51. Gebhardt C, Nemeth J, Angel P, et al., S100A8 and S100A9 in inflammation and cancer, Biochem Pharmacol, 2006;72:1622–31.
  52. Sinha P, Okoro C, Foell D, et al., Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells, J Immunol, 2008;181:4666–75.
  53. Ichikawa M, Williams R, Wang L, et al., S100A8/A9 activate key genes and pathways in colon tumor progression, Mol Cancer Res, 2011;9:133–48.
  54. Markowitz J, Carson WE, 3rd, Review of S100A9 biology and its role in cancer, Biochim Biophys Acta, 2013;1835:100–9.
  55. Lukanidin E, Sleeman JP, Building the niche: the role of the S100 proteins in metastatic growth, Semin Cancer Biol, 2012;22:216–25.
  56. Turovskaya O, Foell D, Sinha P, et al., RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitisassociated carcinogenesis, Carcinogenesis, 2008;29:2035–43.
  57. Rafii S, Lyden D, S100 chemokines mediate bookmarking of premetastatic niches, Nat Cell Biol, 2006;8:1321–3.
  58. Hiratsuka S, Watanabe A, Aburatani H, et al., Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis, Nat Cell Biol, 2006;8:1369–75.
  59. Hiratsuka S, Watanabe A, Sakurai Y, et al., The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a premetastatic phase, Nat Cell Biol, 2008;10:1349–55.
  60. Hibino T, Sakaguchi M, Miyamoto S, et al., S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis, Cancer Res, 2013;73:172–83.
  61. Hermani A, Hess J, De Servi B, et al., Calcium-binding proteins S100A8 and S100A9 as novel diagnostic markers in human prostate cancer, Clin Cancer Res, 2005;11:5146–52.
  62. Grebhardt S, Veltkamp C, Strobel P, et al., Hypoxia and HIF-1 increase S100A8 and S100A9 expression in prostate cancer, Int J Cancer, 2012;131:2785–94.
  63. Grebhardt S, Muller-Decker K, Bestvater F, et al., Impact of S100A8/A9 expression on prostate cancer progression in vitro and in vivo, J Cell Physiol, 2014;229:661–71.
  64. Kallberg E, Vogl T, Liberg D, et al., S100A9 interaction with TLR4 promotes tumor growth, PLoS One, 2012;7:e34207.
  65. Elangovan I, Thirugnanam S, Chen A, et al., Targeting receptor for advanced glycation end products (RAGE) expression induces apoptosis and inhibits prostate tumor growth, Biochem Biophys Res Commun, 2012;417:1133–8.
  66. Saylor PJ, Armstrong AJ, Fizazi K, et al., New and emerging therapies for bone metastases in genitourinary cancers, Eur Urol, 2013;63:309–20.
  67. Thakur A, Vaishampayan U, Lum LG, Immunotherapy and immune evasion in prostate cancer, Cancers (Basel), 2013;5:569–90.
  68. Cha E, Small EJ, Is there a role for immune checkpoint blockade with ipilimumab in prostate cancer?, Cancer Med, 2013;2:243–52.
  69. Phase 3 study of immunotherapy to treat advanced prostate cancer. Available at: 57810?term=NCT01057810&rank=1 (accessed 22 November 2013).
  70. Kwon ED, Drake CG, Scher HI, et al., Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial, Lancet Oncol, 2014;15:700–12.
  71. Raymond E, Dalgleish A, Damber JE, et al., Mechanisms of action of tasquinimod on the tumour microenvironment, Cancer Chemother Pharmacol, 2014;73:1–8.
  72. Jennbacken K, Welen K, Olsson A, et al., Inhibition of metastasis in a castration resistant prostate cancer model by the quinoline-3-carboxamide tasquinimod (ABR-215050), Prostate, 2012;72:913–24.
  73. Leanderson T, Ivars F, S100A9 and tumor growth, Oncoimmunology, 2012;1:1404–5.
  74. Bjork P, Bjork A, Vogl T, et al., Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides, PLoS Biol, 2009;7:e97.
  75. Shen L, Ciesielski M, Miles KM, et al., Abstract 4746: Modulation of suppressive myeloid populations by tasquinimod, Cancer Res, 2013;73(Suppl. 1.).
  76. Isaacs JT, Antony L, Dalrymple SL, et al., Tasquinimod Is an Allosteric Modulator of HDAC4 survival signaling within the compromised cancer microenvironment, Cancer Res, 2013;73:1386–99.
  77. Olsson A, Bjork A, Vallon-Christersson J, et al., Tasquinimod (ABR-215050), a quinoline-3-carboxamide anti-angiogenic agent, modulates the expression of thrombospondin-1 in human prostate tumors, Mol Cancer, 2010;9:107.
  78. Pili R, Haggman M, Stadler WM, et al., Phase II randomized, double-blind, placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer, J Clin Oncol, 2011;29:4022–8.
  79. Armstrong AJ, Haggman M, Stadler WM, et al., Long-term survival and biomarker correlates of tasquinimod efficacy in a multicenter randomized study of men with minimally symptomatic metastatic castration-resistant prostate cancer, Clin Cancer Res, 2013;19:6891–901.
  80. A study of tasquinimod in men with metastatic castrate resistant prostate cancer. Available at: show/NCT01234311 (accessed 15 November 2013).
  81. A proof of concept study of maintenance therapy with tasquinimod in patients with metastatic castrate-resistant prostate cancer who are not progressing after a first line docetaxel based chemotherapy. Avaialble at: http:// (accessed 6 June 2014).
  82. Dalrymple SL, Becker RE, Isaacs JT, The quinoline-3- carboxamide anti-angiogenic agent, tasquinimod, enhances the anti-prostate cancer efficacy of androgen ablation and taxotere without effecting serum PSA directly in human xenografts, Prostate, 2007;67:790–7.
  83. Shen l, Ciesielski M, Miles K, et al, Targeting myeloid derived suppressor cells as novel strategy to enhance immunotherapy in murine prostate cancer models. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; Mar 31–Apr 4 2012; Chicago, Il, Cancer Res, 2012;72(8 Suppl. 1):Abstract 1551.
  84. Dalrymple SL, Becker RE, Zhou H, et al., Tasquinimod prevents the angiogenic rebound induced by fractionated radiation resulting in an enhanced therapeutic response of prostate cancer xenografts, Prostate, 2012;72:638–48.
  85. Finke J, Ko J, Rini B, et al., MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy, Int Immunopharmacol, 2011;11:856–61.
  86. Lunt SJ, Chaudary N, Hill RP, The tumor microenvironment and metastatic disease, Clin Exp Metastasis, 2009;26:19–34.
  87. Murdoch C, Muthana M, Coffelt SB, et al., The role of myeloid cells in the promotion of tumour angiogenesis, Nat Rev Cancer, 2008;8:618–31.
  88. Small AC, Oh WK, Bevacizumab treatment of prostate cancer, Expert Opin Biol Ther, 2012;12:1241–9.
  89. Kelly WK, Halabi S, Carducci M, et al., Randomized, doubleblind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401, J Clin Oncol, 2012;30:1534–40.
  90. Dror Michaelson M, Regan MM, Oh WK, et al., Phase II study of sunitinib in men with advanced prostate cancer, Ann Oncol, 2009;20:913–20.
  91. Mardjuadi F, Medioni J, Kerger J, et al., Phase I study of sorafenib in combination with docetaxel and prednisone in chemo-naive patients with metastatic castration-resistant prostate cancer, Cancer Chemother Pharmacol, 2012;70:293–303.
  92. Rosenberg A, Mathew P, Imatinib and prostate cancer: lessons learned from targeting the platelet-derived growth factor receptor, Expert Opin Investig Drugs, 2013;22:787–94.
  93. Alphonso A, Alahari SK, Stromal cells and integrins: conforming to the needs of the tumor microenvironment, Neoplasia, 2009;11:1264–71.
  94. Danen EH, Integrin signaling as a cancer drug target, IRSN Cell Biology, 2013;2013: Article ID 135164.
  95. Bradley DA, Daignault S, Ryan CJ, et al., Cilengitide (EMD 121974, NSC 707544) in asymptomatic metastatic castration resistant prostate cancer patients: a randomized phase II trial by the prostate cancer clinical trials consortium, Invest New Drugs, 2011;29:1432–40.
  96. Higano CS, Understanding treatments for bone loss and bone metastases in patients with prostate cancer: a practical review and guide for the clinician, Urol Clin North Am, 2004;31:331–52.
  97. Fizazi K, Yang J, Peleg S, et al., Prostate cancer cells-osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts, Clin Cancer Res, 2003;9:2587–97.
  98. Loriot Y, Massard C, Fizazi K, Recent developments in treatments targeting castration-resistant prostate cancer bone metastases, Ann Oncol, 2012;23:1085–94.
  99. Body JJ, Lipton A, Gralow J, et al., Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure, J Bone Miner Res, 2010;25:440–6.
  100. Fizazi K, Bosserman L, Gao G, et al., Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial, J Urol, 2013;189:S51–7; discussion S7–8.
  101. Fizazi K, Carducci M, Smith M, et al., Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study, Lancet, 2011;377:813–22.
  102. Smith MR, Saad F, Oudard S, et al., Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time, J Clin Oncol, 2013;31:3800–6.
  103. Smith MR, Saad F, Coleman R, et al., Denosumab and bonemetastasis- free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebocontrolled trial, Lancet, 2012;379:39–46.
  104. Sartor AO, Heinrich D, Helle SI, et al. , Radium-223 chloride impact on skeletal-related events in patients with castrationresistant prostate cancer (CRPC) with bone metastases: a phase III randomized trial (ALSYMPCA), J Clin Oncol, 2012;30 (Suppl 5):Abstract 9.
  105. Parker C, Heinrich D, O’Sullivan JM, et al., Overall survival benefit and safety profile of radium-223 chloride, a firstin- class alpha- pharmaceutical: results from a phase III randomized trial (ALSYMPCA) in patients with castrationresistant prostate cancer (CRPC) with bone metastases., J Clin Oncol, 2012;30(Suppl. 5) Abstr 8.
  106. Trump DL, Commentary on “Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial.” Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, Vogelzang NJ, Small EJ, Harzstark AL, Gordon MS, Vaishampayan UN, Haas NB, Spira AI, Lara PN Jr, Lin CC, Srinivas S, Sella A, Schoffski P, Scheffold C, Weitzman AL, Hussain M, University of Michigan, Ann Arbor, MI, J Clin Oncol, 2013;31:412–9.
  107. Smith DC, Smith MR, Sweeney C, et al., Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial, J Clin Oncol, 2013;31:412–9.
  108. Msaouel P, Nandikolla G, Pneumaticos SG, et al., Bone microenvironment-targeted manipulations for the treatment of osteoblastic metastasis in castration-resistant prostate cancer, Expert Opin Investig Drugs, 2013;22:1385–400.
  109. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial, Lancet Oncol, 2014;15:700-712.
Keywords: Castrate-resistant prostate cancer, immunosuppression, ipilimumab, tumour microenvironment, myeloid-derived suppressor cells, S100A9, tumour-associated macrophages, radium-223, sipuleucel T, tasquinimod