Osteoimmuno-Oncology: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Tiina Kähkönen.

Osteoimmuno-oncology (OIO) refers to interactions between bone, immune and tumor cells in bone metastatic microenvironment. Understanding the interplay between these three separate but tightly linked compartments is essential when developing novel therapies for bone metastases. OIO is based on two well established concepts: osteoimmunology and immuno-oncology that are now combined in OIO.

  • osteoimmuno-oncology
  • immuno-oncology
  • osteoimmunology
  • immunotherapy
  • bone metastasis
Please wait, diff process is still running!

References

  1. Owen, K.L.; Parker, B.S. Beyond the vicious cycle: The role of innate osteoimmunity, automimicry and tumor-inherent changes in dictating bone metastasis. Mol. Immunol. 2019, 110, 57–68.
  2. Fournier, P.; Chirgwin, J.M.; Guise, T.A. New insights into the role of T cells in the vicious cycle of bone metastases. Curr. Opin. Rheumatol. 2006, 18, 396–404.
  3. Li, Z.; Zhang, L.-J.; Zhang, H.-R.; Tian, G.-F.; Tian, J.; Mao, X.-L.; Jia, Z.-H.; Meng, Z.-Y.; Zhao, L.-Q.; Yin, Z.-N.; et al. Tumor-derived transforming growth factor-β is critical for tumor progression and evasion from immune surveillance. Asian Pac. J. Cancer Prev. 2014, 15, 5181–5186.
  4. D’Amico, L.; Roato, I. The Impact of Immune System in Regulating Bone Metastasis Formation by Osteotropic Tumors. J. Immunol. Res. 2015, 2015, 143526.
  5. Zhao, E.; Xu, H.; Wang, L.; Kryczek, I.; Wu, K.; Hu, Y.; Wang, G.; Zou, W. Bone marrow and the control of immunity. Cell. Mol. Immunol. 2011, 9, 11–19.
  6. Wang, H.Y.; Zhou, J.; Zhu, K.; Riker, A.I.; Marincola, F.M.; Wang, R.-F. Identification of a Mutated Fibronectin As a Tumor Antigen Recognized by CD4+T Cells: Its Role in Extracellular Matrix Formation and Tumor Metastasis. J. Exp. Med. 2002, 195, 1397–1406.
  7. Bidwell, B.N.; Slaney, C.Y.; Withana, N.P.; Forster, S.; Cao, Y.; Loi, S.; Andrews, D.; Mikeska, T.; Mangan, N.E.; Samarajiwa, S.A.; et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat. Med. 2012, 18, 1224–1231.
  8. Lengagne, R.; Graff-Dubois, S.; Garcette, M.; Renia, L.; Kato, M.; Guillet, J.-G.; Engelhard, V.H.; Avril, M.-F.; Abastado, J.-P.; Prévost-Blondel, A. Distinct role for CD8 T cells toward cutaneous tumors and visceral metastases. J. Immunol. 2007, 180, 130–137.
  9. Vidotto, T.; Saggioro, F.P.; Jamaspishvili, T.; Chesca, D.L.; De Albuquerque, C.G.P.; Reis, R.B.; Graham, C.H.; Berman, D.M.; Siemens, D.R.; Squire, J.A.; et al. PTEN-deficient prostate cancer is associated with an immunosuppressive tumor microenvironment mediated by increased expression of IDO1 and infiltrating FoxP3+ T regulatory cells. Prostate 2019, 79, 969–979.
  10. Xiang, L.; Gilkes, D.M. The Contribution of the Immune System in Bone Metastasis Pathogenesis. Int. J. Mol. Sci. 2019, 20, 999.
  11. Barnett, J.C.; Bean, S.M.; Whitaker, R.S.; Kondoh, E.; Baba, T.; Fujii, S.; Marks, J.R.; Dressman, H.K.; Murphy, S.; Berchuck, A. Ovarian cancer tumor infiltrating T-regulatory (Treg) cells are associated with a metastatic phenotype. Gynecol. Oncol. 2010, 116, 556–562.
  12. Karavitis, J.; Hix, L.M.; Shi, Y.H.; Schultz, R.F.; Khazaie, K.; Zhang, M. Regulation of COX2 Expression in Mouse Mammary Tumor Cells Controls Bone Metastasis and PGE2-Induction of Regulatory T Cell Migration. PLoS ONE 2012, 7, e46342.
  13. Hix, L.M.; Shi, Y.H.; Brutkiewicz, R.R.; Stein, P.L.; Wang, C.-R.; Zhang, M. CD1d-Expressing Breast Cancer Cells Modulate NKT Cell-Mediated Antitumor Immunity in a Murine Model of Breast Cancer Metastasis. PLoS ONE 2011, 6, e20702.
  14. Liu, G.; Lu, S.; Wang, X.; Page, S.T.; Higano, C.S.; Plymate, S.R.; Greenberg, N.M.; Sun, S.; Li, Z.; Wu, J.D. Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis. J. Clin. Investig. 2013, 123, 4410–4422.
  15. Mittal, D.; Vijayan, D.; Putz, E.M.; Aguilera, A.R.; Markey, K.A.; Straube, J.; Kazakoff, S.; Nutt, S.L.; Takeda, K.; Hill, G.R.; et al. Interleukin-12 from CD103+ Batf3-Dependent Dendritic Cells Required for NK-Cell Suppression of Metastasis. Cancer Immunol. Res. 2017, 5, 1098–1108.
  16. Jewett, A.; Kos, J.; Fong, Y.; Ko, M.-W.; Safaei, T.; Nanut, M.P.; Kaur, K. NK cells shape pancreatic and oral tumor microenvironments; role in inhibition of tumor growth and metastasis. Semin. Cancer Biol. 2018, 53, 178–188.
  17. Rautela, J.; Baschuk, N.; Slaney, C.Y.; Jayatilleke, K.M.; Xiao, K.; Bidwell, B.N.; Lucas, E.C.; Hawkins, E.; Lock, P.; Wong, C.S.; et al. Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer. Cancer Immunol. Res. 2015, 3, 1207–1217.
  18. Wang, Y.; Ding, Y.; Guo, N.; Wang, S. MDSCs: Key Criminals of Tumor Pre-metastatic Niche Formation. Front. Immunol. 2019, 10, 172.
  19. Souza-Fonseca-Guimaraes, F.; Young, A.; Mittal, D.; Martinet, L.; Bruedigam, C.; Takeda, K.; Andoniou, C.; Degli-Esposti, M.A.; Hill, G.; Smyth, M.J. NK cells require IL-28R for optimal in vivo activity. Proc. Natl. Acad. Sci. USA 2015, 112, E2376–E2384.
  20. Zhang, H.; Yano, S.; Miki, T.; Goto, H.; Kanematsu, T.; Muguruma, H.; Uehara, H.; Sone, S. A novel bisphosphonate minodronate (YM529) specifically inhibits osteolytic bone metastasis produced by human small-cell lung cancer cells in NK-cell depleted SCID mice. Clin. Exp. Metastasis 2003, 20, 153–159.
  21. Bottos, A.; Gotthardt, D.; Gill, J.W.; Gattelli, A.; Frei, A.; Tzankov, A.; Sexl, V.; Wodnar-Filipowicz, A.; Hynes, N.E. Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models. Nat. Commun. 2016, 7, 12258.
  22. Biswas, S.; Nyman, J.S.; Alvarez, J.; Chakrabarti, A.; Ayres, A.; Sterling, J.; Edwards, J.; Rana, T.; Johnson, R.; Perrien, D.S.; et al. Anti-Transforming Growth Factor ß Antibody Treatment Rescues Bone Loss and Prevents Breast Cancer Metastasis to Bone. PLoS ONE 2011, 6, e27090.
  23. Zhang, J.; Qiu, X.; Zhang, N.; Tang, W.; Gober, H.; Li, D.; Wang, L. Bu-Shen-Ning-Xin decoction suppresses osteoclastogenesis by modulating RANKL/OPG imbalance in the CD4+ T lymphocytes of ovariectomized mice. Int. J. Mol. Med. 2018, 42, 299–308.
  24. Ye, X.-Z.; Yu, S.-C.; Bian, X.-W. Contribution of myeloid-derived suppressor cells to tumor-induced immune suppression, angiogenesis, invasion and metastasis. J. Genet. Genom. 2010, 37, 423–430.
  25. Bergenfelz, C.; Roxå, A.; Mehmeti, M.; Leandersson, K.; Larsson, A.-M. Clinical relevance of systemic monocytic-MDSCs in patients with metastatic breast cancer. Cancer Immunol. Immunother. 2020, 69, 435–448.
  26. Bosiljcic, M.; Cederberg, R.A.; Hamilton, M.J.; LePard, N.E.; Harbourne, B.T.; Collier, J.L.; Halvorsen, E.C.; Shi, R.; Franks, S.E.; Kim, A.Y.; et al. Targeting myeloid-derived suppressor cells in combination with primary mammary tumor resection reduces metastatic growth in the lungs. Breast Cancer Res. 2019, 21, 103.
  27. Wei, W.-C.; Lin, S.-Y.; Lan, C.-W.; Huang, Y.-C.; Lin, C.-Y.; Hsiao, P.-W.; Chen, Y.-R.; Yang, W.-C.; Yang, N.-S. Inhibiting MDSC differentiation from bone marrow with phytochemical polyacetylenes drastically impairs tumor metastasis. Sci. Rep. 2016, 6, 36663.
  28. Cao, Y.; Slaney, C.Y.; Bidwell, B.N.; Parker, B.S.; Johnstone, C.N.; Rautela, J.; Eckhardt, B.L.; Anderson, R.L. BMP4 Inhibits Breast Cancer Metastasis by Blocking Myeloid-Derived Suppressor Cell Activity. Cancer Res. 2014, 74, 5091–5102.
  29. Ma, Y.; Zhao, N.; Liu, G. Conjugate (MTC-220) of Muramyl Dipeptide Analogue and Paclitaxel Prevents Both Tumor Growth and Metastasis in Mice. J. Med. Chem. 2011, 54, 2767–2777.
  30. Moon, E.-Y.; Ryu, Y.-K.; Lee, G.-H. Dexamethasone inhibits in vivo tumor growth by the alteration of bone marrow CD11b+ myeloid cells. Int. Immunopharmacol. 2014, 21, 494–500, Erratum in 2014, 22, 526–527.
  31. Sawant, A.; Ponnazhagan, S. Myeloid-Derived Suppressor Cells as Osteoclast Progenitors: A Novel Target for Controlling Osteolytic Bone Metastasis. Cancer Res. 2013, 73, 4606–4610.
  32. Lee, S.-H.; Kim, T.-S.; Choi, Y.-W.; Lorenzo, J. Osteoimmunology: Cytokines and the skeletal system. BMB Rep. 2008, 41, 495–510.
  33. Martínez, V.G.; Rubio, C.; Martínez-Fernández, M.; Segovia, C.; López-Calderón, F.; Garín, M.I.; Teijeira, A.; Munera-Maravilla, E.; Varas, A.; Sacedón, R.; et al. BMP4 Induces M2 Macrophage Polarization and Favors Tumor Progression in Bladder Cancer. Clin. Cancer Res. 2017, 23, 7388–7399.
  34. Niu, Z.; Shi, Q.; Zhang, W.; Shu, Y.; Yang, N.; Chen, B.; Wang, Q.; Zhao, X.; Chen, J.; Cheng, N.; et al. Caspase-1 cleaves PPARγ for potentiating the pro-tumor action of TAMs. Nat. Commun. 2017, 8, 766.
  35. Buddingh, E.; Kuijjer, M.; Duim, R.A.; Bürger, H.; Agelopoulos, K.; Myklebost, O.; Serra, M.; Mertens, F.; Hogendoorn, P.; Lankester, A.C.; et al. Tumor-Infiltrating Macrophages Are Associated with Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment with Macrophage Activating Agents. Clin. Cancer Res. 2011, 17, 2110–2119.
  36. Takiguchi, S.; Korenaga, N.; Inoue, K.; Sugi, E.; Kataoka, Y.; Matsusue, K.; Futagami, K.; Li, Y.-J.; Kukita, T.; Teramoto, N.; et al. Involvement of CXCL14 in osteolytic bone metastasis from lung cancer. Int. J. Oncol. 2014, 44, 1316–1324.
  37. Hiraoka, K.; Zenmyo, M.; Watari, K.; Iguchi, H.; Fotovati, A.; Kimura, Y.N.; Hosoi, F.; Shoda, T.; Nagata, K.; Osada, H.; et al. Inhibition of bone and muscle metastases of lung cancer cells by a decrease in the number of monocytes/macrophages. Cancer Sci. 2008, 99, 1595–1602.
  38. Jones, J.; Sinder, B.; Paige, D.; Soki, F.; Koh, A.; Thiele, S.; Shiozawa, Y.; Hofbauer, L.; Daignault, S.; Roca, H.; et al. Trabectedin Reduces Skeletal Prostate Cancer Tumor Size in Association with Effects on M2 Macrophages and Efferocytosis. Neoplasia 2019, 21, 172–184.
  39. Jing, W.; Guo, X.; Wang, G.; Bi, Y.; Han, L.; Zhu, Q.; Qiu, C.; Tanaka, M.; Zhao, Y. Breast cancer cells promote CD169+ macrophage-associated immunosuppression through JAK2-mediated PD-L1 upregulation on macrophages. Int. Immunopharmacol. 2020, 78, 106012.
  40. Shrivastava, R.; Asif, M.; Singh, V.; Dubey, P.; Malik, S.A.; Lone, M.-U.-D.; Tewari, B.N.; Baghel, K.S.; Pal, S.; Nagar, G.K.; et al. M2 polarization of macrophages by Oncostatin M in hypoxic tumor microenvironment is mediated by mTORC2 and promotes tumor growth and metastasis. Cytokine 2019, 118, 130–143.
  41. Wu, A.C.; He, Y.; Broomfield, A.; Paatan, N.J.; Harrington, B.S.; Tseng, H.-W.; Beaven, E.A.; Kiernan, D.M.; Swindle, P.; Clubb, A.B.; et al. CD169+macrophages mediate pathological formation of woven bone in skeletal lesions of prostate cancer. J. Pathol. 2016, 239, 218–230.
  42. Tourkova, I.L.; Yamabe, K.; Chatta, G.; Shurin, G.V.; Shurin, M. NK Cells Mediate Flt3 Ligand-Induced Protection of Dendritic Cell Precursors In Vivo from the Inhibition by Prostate Carcinoma in the Murine Bone Marrow Metastasis Model. J. Immunother. 2003, 26, 468–472.
  43. Imai, K.; Minamiya, Y.; Koyota, S.; Ito, M.; Saito, H.; Satoru, M.; Motoyama, S.; Sugiyama, T.; Ogawa, J.-I. Inhibition of dendritic cell migration by transforming growth factor-β1 increases tumor-draining lymph node metastasis. J. Exp. Clin. Cancer Res. 2012, 31, 3.
  44. Tanaka, H.; Shinto, O.; Yashiro, M.; Yamazoe, S.; Iwauchi, T.; Muguruma, K.; Kubo, N.; Ohira, M.; Hirakawa, K. Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity. Oncol. Rep. 2010, 24, 1637–1643.
  45. Liu, J.; Li, J.; Fan, Y.; Chang, K.; Yang, X.; Zhu, W.; Wu, X.; Pang, Y. Concurrent dendritic cell vaccine and strontium-89 radiation therapy in the management of multiple bone metastases. Ir. J. Med Sci. 2014, 184, 457–461.
  46. Kawano, M.; Itonaga, I.; Iwasaki, T.; Tsumura, H. Enhancement of antitumor immunity by combining anti-cytotoxic T lymphocyte antigen-4 antibodies and cryotreated tumor lysate-pulsed dendritic cells in murine osteosarcoma. Oncol. Rep. 2013, 29, 1001–1006.
  47. Bonavita, O.; Massara, M.; Bonecchi, R. Chemokine regulation of neutrophil function in tumors. Cytokine Growth Factor Rev. 2016, 30, 81–86.
  48. Massara, M.; Bonavita, O.; Savino, B.; Caronni, N.; Poeta, V.M.; Sironi, M.; Setten, E.; Recordati, C.; Crisafulli, L.; Ficara, F.; et al. ACKR2 in hematopoietic precursors as a checkpoint of neutrophil release and anti-metastatic activity. Nat. Commun. 2018, 9, 676.
  49. Jablonska, J.; Lang, S.; Sionov, R.V.; Granot, Z. The regulation of pre-metastatic niche formation by neutrophils. Oncotarget 2017, 8, 112132–112144.
  50. Patel, S.; Fu, S.; Mastio, J.; Dominguez, G.A.; Purohit, A.; Kossenkov, A.; Lin, C.; Alicea-Torres, K.; Sehgal, M.; Nefedova, Y.; et al. Unique pattern of neutrophil migration and function during tumor progression. Nat. Immunol. 2018, 19, 1236–1247.
  51. Costanzo-Garvey, D.L.; Keeley, T.; Case, A.J.; Watson, G.F.; Alsamraae, M.; Yu, Y.; Su, K.; Heim, C.E.; Kielian, T.; Morrissey, C.; et al. Neutrophils are mediators of metastatic prostate cancer progression in bone. Cancer Immunol. Immunother. 2020, 69, 1113–1130.
  52. Qiu, X.; Gui, Y.; Xu, Y.; Li, D.; Wang, L. DHEA promotes osteoblast differentiation by regulating the expression of osteoblast-related genes and Foxp3(+) regulatory T cells. Biosci. Trends 2015, 9, 307–314.
  53. Li, S.; Li, T.; Chen, Y.; Nie, Y.; Li, C.; Liu, L.; Li, Q.; Qiu, L. Granulocyte Colony-Stimulating Factor Induces Osteoblast Inhibition by B Lymphocytes and Osteoclast Activation by T Lymphocytes during Hematopoietic Stem/Progenitor Cell Mobilization. Biol. Blood Marrow Transpl. 2015, 21, 1384–1391.
  54. Panaroni, C.; Wu, J.Y. Interactions Between B Lymphocytes and the Osteoblast Lineage in Bone Marrow. Calcif. Tissue Int. 2013, 93, 261–268.
  55. Cain, C.J.; Rueda, R.; McLelland, B.; Collette, N.M.; Loots, G.G.; Manilay, J.O. Absence of sclerostin adversely affects B-cell survival. J. Bone Miner. Res. 2012, 27, 1451–1461.
  56. Mansour, A.; Anginot, A.; Mancini, S.J.C.; Schiff, C.; Carle, G.F.; Wakkach, A.; Blin-Wakkach, C. Osteoclast activity modulates B-cell development in the bone marrow. Cell Res. 2011, 21, 1102–1115.
  57. Panaroni, C.; Fulzele, K.; Saini, V.; Chubb, R.; Pajevic, P.D.; Wu, J.Y. PTH Signaling in Osteoprogenitors Is Essential for B-Lymphocyte Differentiation and Mobilization. J. Bone Miner. Res. 2015, 30, 2273–2286.
  58. Takayanagi, H.; Ogasawara, K.; Hida, S.; Chiba, T.; Murata, S.; Sato, K.; Takaoka, A.; Yokochi, T.; Oda, H.; Tanaka, K.; et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 2000, 408, 600–605.
  59. Fumoto, T.; Takeshita, S.; Ito, M.; Ikeda, K. Physiological Functions of Osteoblast Lineage and T Cell-Derived RANKL in Bone Homeostasis. J. Bone Miner. Res. 2014, 29, 830–842.
  60. Zhang, J.; Qiu, X.; Zhang, N.; Tang, W.; Gober, H.; Li, D.; Wang, L. Bu-Shen-Ning-Xin decoction suppresses osteoclastogenesis by modulating RANKL/OPG imbalance in the CD4+ T lymphocytes of ovariectomized mice. Int. J. Mol. Med. 2018, 42, 299–308.
  61. Manabe, N.; Kawaguchi, H.; Chikuda, H.; Miyaura, C.; Inada, M.; Nagai, R.; Nabeshima, Y.-I.; Nakamura, K.; Sinclair, A.M.; Scheuermann, R.H.; et al. Connection Between B Lymphocyte and Osteoclast Differentiation Pathways. J. Immunol. 2001, 167, 2625–2631.
  62. Francisconi, C.; Vieira, A.E.; Azevedo, M.D.C.S.; Tabanez, A.; Fonseca, A.; Trombone, A.; Letra, A.; Silva, R.; Sfeir, C.; Little, S.; et al. RANKL Triggers Treg-Mediated Immunoregulation in Inflammatory Osteolysis. J. Dent. Res. 2018, 97, 917–927.
  63. Tilkeridis, K.; Kiziridis, G.; Ververidis, A.; Papoutselis, M.; Kotsianidis, I.; Kitsikidou, G.; Tousiaki, N.-E.; Drosos, G.; Kapetanou, A.; Rechova, K.V.; et al. Immunoporosis: A New Role for Invariant Natural Killer T (NKT) Cells Through Overexpression of Nuclear Factor-κB Ligand (RANKL). Med. Sci. Monit. 2019, 25, 2151–2158.
  64. Horowitz, M.C.; Bothwell, A.L.M.; Hesslein, D.G.T.; Pflugh, D.L.; Schatz, D.G. B cells and osteoblast and osteoclast development. Immunol. Rev. 2005, 208, 141–153.
  65. Fujiwara, Y.; Piemontese, M.; Liu, Y.; Thostenson, J.D.; Xiong, J.; O’Brien, C.A. RANKL (Receptor Activator of NFκB Ligand) Produced by Osteocytes Is Required for the Increase in B Cells and Bone Loss Caused by Estrogen Deficiency in Mice. J. Biol. Chem. 2016, 291, 24838–24850.
  66. Lee, S.-H.; Kim, T.-S.; Choi, Y.-W.; Lorenzo, J. Osteoimmunology: Cytokines and the skeletal system. BMB Rep. 2008, 41, 495–510.
  67. Coleman, R.E.; Croucher, P.I.; Padhani, A.R.; Clézardin, P.; Chow, E.; Fallon, M.; Guise, T.; Colangeli, S.; Capanna, R.; Costa, L. Bone metastases. Nat. Rev. Dis. Prim. 2020, 6, 1–28.
  68. Owen, K.L.; Parker, B.S. Beyond the vicious cycle: The role of innate osteoimmunity, automimicry and tumor-inherent changes in dictating bone metastasis. Mol. Immunol. 2019, 110, 57–68.
  69. Antonarakis, E.S.; Piulats, J.M.; Gross-Goupil, M.; Goh, J.; Ojamaa, K.; Hoimes, C.J.; Vaishampayan, U.; Berger, R.; Sezer, A.; Alanko, T.; et al. Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J. Clin. Oncol. 2020, 38, 395–405.
  70. Luo, G.; He, Y.; Zhao, Q.; Yu, X. Immune Cells Act as Promising Targets for the Treatment of Bone Metastasis. Recent Pat. Anti-Cancer Drug Discov. 2017, 12, 221–233.
  71. Marin-Acevedo, J.A.; Soyano, A.E.; Dholaria, B.; Knutson, K.L.; Lou, Y. Cancer immunotherapy beyond immune checkpoint inhibitors. J. Hematol. Oncol. 2018, 11, 8.
  72. Stefanovic, S.; Schuetz, F.; Sohn, C.; Beckhove, P.; Domschke, C. Adoptive immunotherapy of metastatic breast cancer: Present and future. Cancer Metastasis Rev. 2013, 33, 309–320.
  73. Monteiro, A.C.; Leal, A.C.; Gonçalves-Silva, T.; Mercadante, A.C.T.; Kestelman, F.; Chaves, S.; Azevedo, R.B.; Monteiro, J.P.; Bonomo, A. T Cells Induce Pre-Metastatic Osteolytic Disease and Help Bone Metastases Establishment in a Mouse Model of Metastatic Breast Cancer. PLoS ONE 2013, 8, e68171.
  74. Fournier, P.; Chirgwin, J.M.; Guise, T.A. New insights into the role of T cells in the vicious cycle of bone metastases. Curr. Opin. Rheumatol. 2006, 18, 396–404.
  75. Correale, P.; Micheli, L.; Del Vecchio, M.T.; Sabatino, M.; Petrioli, R.; Pozzessere, D.; Marsili, S.; Giorgi, G.; Lozzi, L.; Neri, P.; et al. A parathyroid-hormone-related-protein (PTH-rP)-specific cytotoxic T cell response induced by in vitro stimulation of tumour-infiltrating lymphocytes derived from prostate cancer metastases, with epitope peptide-loaded autologous dendritic cells and low-dose IL-2. Br. J. Cancer 2001, 85, 1722–1730.
  76. Li, Z.; Zhang, L.-J.; Zhang, H.-R.; Tian, G.-F.; Tian, J.; Mao, X.-L.; Jia, Z.-H.; Meng, Z.-Y.; Zhao, L.-Q.; Yin, Z.-N.; et al. Tumor-derived transforming growth factor-β is critical for tumor progression and evasion from immune surveillance. Asian Pac. J. Cancer Prev. 2014, 15, 5181–5186.
  77. D’Amico, L.; Roato, I. The Impact of Immune System in Regulating Bone Metastasis Formation by Osteotropic Tumors. J. Immunol. Res. 2015, 2015, 143526.
  78. Domschke, C.; Ge, Y.; Bernhardt, I.; Schott, S.; Keim, S.; Juenger, S.; Bucur, M.; Mayer, L.; Blumenstein, M.; Rom, J.; et al. Long-term survival after adoptive bone marrow T cell therapy of advanced metastasized breast cancer: Follow-up analysis of a clinical pilot trial. Cancer Immunol. Immunother. 2013, 62, 1053–1060.
  79. Wang, H.Y.; Zhou, J.; Zhu, K.; Riker, A.I.; Marincola, F.M.; Wang, R.-F. Identification of a Mutated Fibronectin As a Tumor Antigen Recognized by CD4+T Cells: Its Role in Extracellular Matrix Formation and Tumor Metastasis. J. Exp. Med. 2002, 195, 1397–1406.
  80. Juric, V.; O’Sullivan, C.; Stefanutti, E.; Kovalenko, M.; Greenstein, A.; Barry-Hamilton, V.; Mikaelian, I.; Degenhardt, J.; Yue, P.; Smith, V.; et al. MMP-9 inhibition promotes anti-tumor immunity through disruption of biochemical and physical barriers to T-cell trafficking to tumors. PLoS ONE 2018, 13, e0207255.
  81. Bidwell, B.N.; Slaney, C.Y.; Withana, N.P.; Forster, S.; Cao, Y.; Loi, S.; Andrews, D.; Mikeska, T.; Mangan, N.E.; Samarajiwa, S.A.; et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat. Med. 2012, 18, 1224–1231.
  82. Lengagne, R.; Graff-Dubois, S.; Garcette, M.; Renia, L.; Kato, M.; Guillet, J.-G.; Engelhard, V.H.; Avril, M.-F.; Abastado, J.-P.; Prévost-Blondel, A. Distinct role for CD8 T cells toward cutaneous tumors and visceral metastases. J. Immunol. 2007, 180, 130–137.
  83. Vidotto, T.; Saggioro, F.P.; Jamaspishvili, T.; Chesca, D.L.; De Albuquerque, C.G.P.; Reis, R.B.; Graham, C.H.; Berman, D.M.; Siemens, D.R.; Squire, J.A.; et al. PTEN-deficient prostate cancer is associated with an immunosuppressive tumor microenvironment mediated by increased expression of IDO1 and infiltrating FoxP3+ T regulatory cells. Prostate 2019, 79, 969–979.
  84. Xiang, L.; Gilkes, D.M. The Contribution of the Immune System in Bone Metastasis Pathogenesis. Int. J. Mol. Sci. 2019, 20, 999.
  85. Brinkrolf, P.; Landmeier, S.; Altvater, B.; Chen, C.; Pscherer, S.; Rosemann, A.; Ranft, A.; Dirksen, U.; Juergens, H.; Rossig, C. A high proportion of bone marrow T cells with regulatory phenotype (CD4+CD25hiFoxP3+) in Ewing sarcoma patients is associated with metastatic disease. Int. J. Cancer 2009, 125, 879–886.
  86. Barnett, J.C.; Bean, S.M.; Whitaker, R.S.; Kondoh, E.; Baba, T.; Fujii, S.; Marks, J.R.; Dressman, H.K.; Murphy, S.; Berchuck, A. Ovarian cancer tumor infiltrating T-regulatory (Treg) cells are associated with a metastatic phenotype. Gynecol. Oncol. 2010, 116, 556–562.
  87. Karavitis, J.; Hix, L.M.; Shi, Y.H.; Schultz, R.F.; Khazaie, K.; Zhang, M. Regulation of COX2 Expression in Mouse Mammary Tumor Cells Controls Bone Metastasis and PGE2-Induction of Regulatory T Cell Migration. PLoS ONE 2012, 7, e46342.
  88. Hix, L.M.; Shi, Y.H.; Brutkiewicz, R.R.; Stein, P.L.; Wang, C.-R.; Zhang, M. CD1d-Expressing Breast Cancer Cells Modulate NKT Cell-Mediated Antitumor Immunity in a Murine Model of Breast Cancer Metastasis. PLoS ONE 2011, 6, e20702.
  89. Roato, I.; Vitale, M. The Uncovered Role of Immune Cells and NK Cells in the Regulation of Bone Metastasis. Front. Endocrinol. 2019, 10, 145.
  90. Verhoeven, D.H.; de Hooge, A.S.; Mooiman, E.C.; Santos, S.J.; Dam, M.M.T.; Gelderblom, H.; Melief, C.J.; Hogendoorn, P.C.; Egeler, R.M.; van Tol, M.J.; et al. NK cells recognize and lyse Ewing sarcoma cells through NKG2D and DNAM-1 receptor dependent pathways. Mol. Immunol. 2008, 45, 3917–3925.
  91. Liu, G.; Lu, S.; Wang, X.; Page, S.T.; Higano, C.S.; Plymate, S.R.; Greenberg, N.M.; Sun, S.; Li, Z.; Wu, J.D. Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis. J. Clin. Investig. 2013, 123, 4410–4422.
  92. Mittal, D.; Vijayan, D.; Putz, E.M.; Aguilera, A.R.; Markey, K.A.; Straube, J.; Kazakoff, S.; Nutt, S.L.; Takeda, K.; Hill, G.R.; et al. Interleukin-12 from CD103+ Batf3-Dependent Dendritic Cells Required for NK-Cell Suppression of Metastasis. Cancer Immunol. Res. 2017, 5, 1098–1108.
  93. Zhang, H.; Vijayan, D.; Li, X.-Y.; Robson, S.C.; Geetha, N.; Teng, M.W.L.; Smyth, M.J. The role of NK cells and CD39 in the immunological control of tumor metastases. OncoImmunology 2019, 8, e1593809.
  94. Zhao, Y.; Chen, W.; Zhu, W.; Meng, H.; Chen, J.; Zhang, J. Overexpression of Interferon Regulatory Factor 7 (IRF7) Reduces Bone Metastasis of Prostate Cancer Cells in Mice. Oncol. Res. Featur. Preclin. Clin. Cancer Ther. 2017, 25, 511–522.
  95. Jewett, A.; Kos, J.; Fong, Y.; Ko, M.-W.; Safaei, T.; Nanut, M.P.; Kaur, K. NK cells shape pancreatic and oral tumor microenvironments; role in inhibition of tumor growth and metastasis. Semin. Cancer Biol. 2018, 53, 178–188.
  96. Rautela, J.; Baschuk, N.; Slaney, C.Y.; Jayatilleke, K.M.; Xiao, K.; Bidwell, B.N.; Lucas, E.C.; Hawkins, E.; Lock, P.; Wong, C.S.; et al. Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer. Cancer Immunol. Res. 2015, 3, 1207–1217.
  97. Wang, Y.; Ding, Y.; Guo, N.; Wang, S. MDSCs: Key Criminals of Tumor Pre-metastatic Niche Formation. Front. Immunol. 2019, 10, 172.
  98. Souza-Fonseca-Guimaraes, F.; Young, A.; Mittal, D.; Martinet, L.; Bruedigam, C.; Takeda, K.; Andoniou, C.; Degli-Esposti, M.A.; Hill, G.; Smyth, M.J. NK cells require IL-28R for optimal in vivo activity. Proc. Natl. Acad. Sci. USA 2015, 112, E2376–E2384.
  99. Miki, T.; Yano, S.; Hanibuchi, M.; Kanematsu, T.; Muguruma, H.; Sone, S. Parathyroid hormone-related protein (PTHrP) is responsible for production of bone metastasis, but not visceral metastasis, by human small cell lung cancer SBC-5 cells in natural killer cell-depleted SCID mice. Int. J. Cancer 2004, 108, 511–515.
  100. Zhang, H.; Yano, S.; Miki, T.; Goto, H.; Kanematsu, T.; Muguruma, H.; Uehara, H.; Sone, S. A novel bisphosphonate minodronate (YM529) specifically inhibits osteolytic bone metastasis produced by human small-cell lung cancer cells in NK-cell depleted SCID mice. Clin. Exp. Metastasis 2003, 20, 153–159.
  101. Ogino, H.; Yano, S.; Kakiuchi, S.; Muguruma, H.; Ikuta, K.; Hanibuchi, M.; Uehara, H.; Tsuchida, K.; Sugino, H.; Sone, S. Follistatin Suppresses the Production of Experimental Multiple-Organ Metastasis by Small Cell Lung Cancer Cells in Natural Killer Cell–Depleted SCID Mice. Clin. Cancer Res. 2008, 14, 660–667.
  102. Otsuka, S.; Hanibuchi, M.; Ikuta, K.; Yano, S.; Goto, H.; Ogino, H.; Yamada, T.; Kakiuchi, S.; Nishioka, Y.; Takahashi, T.; et al. A Bone Metastasis Model With Osteolytic and Osteoblastic Properties of Human Lung Cancer ACC-LC-319/bone2 in Natural Killer Cell-Depleted Severe Combined Immunodeficient Mice. Oncol. Res. Featur. Preclin. Clin. Cancer Ther. 2009, 17, 581–591.
  103. Bottos, A.; Gotthardt, D.; Gill, J.W.; Gattelli, A.; Frei, A.; Tzankov, A.; Sexl, V.; Wodnar-Filipowicz, A.; Hynes, N.E. Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models. Nat. Commun. 2016, 7, 12258.
  104. Biswas, S.; Nyman, J.S.; Alvarez, J.; Chakrabarti, A.; Ayres, A.; Sterling, J.; Edwards, J.; Rana, T.; Johnson, R.; Perrien, D.S.; et al. Anti-Transforming Growth Factor ß Antibody Treatment Rescues Bone Loss and Prevents Breast Cancer Metastasis to Bone. PLoS ONE 2011, 6, e27090.
  105. Arlauckas, S.P.; Garren, S.B.; Garris, C.S.; Kohler, R.H.; Oh, J.; Pittet, M.J.; Weissleder, R. Arg1 expression defines immunosuppressive subsets of tumor-associated macrophages. Theranostics 2018, 8, 5842–5854.
  106. Jayaraman, P.; Parikh, F.; Lopez-Rivera, E.; Hailemichael, Y.; Clark, A.; Ma, G.; Cannan, D.; Ramacher, M.; Kato, M.; Overwijk, W.W.; et al. Tumor-Expressed Inducible Nitric Oxide Synthase Controls Induction of Functional Myeloid-Derived Suppressor Cells through Modulation of Vascular Endothelial Growth Factor Release. J. Immunol. 2012, 188, 5365–5376.
  107. Wink, D.A.; Ridnour, L.A.; Cheng, R.; Switzer, C.W.; Glynn, S.; Ambs, S. The Oncogenic Properties Of The Redox Inflammatory Protein Inducible Nitric Oxide Synthase In ER(-) Breast Cancer. Redox Biol. 2015, 5, 413.
  108. Groth, C.; Hu, X.; Weber, R.; Fleming, V.; Altevogt, P.; Utikal, J.; Umansky, V. Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression. Br. J. Cancer 2019, 120, 16–25.
  109. Li, B.-H.; Garstka, M.A.; Li, Z.-F. Chemokines and their receptors promoting the recruitment of myeloid-derived suppressor cells into the tumor. Mol. Immunol. 2020, 117, 201–215.
  110. Ye, X.-Z.; Yu, S.-C.; Bian, X.-W. Contribution of myeloid-derived suppressor cells to tumor-induced immune suppression, angiogenesis, invasion and metastasis. J. Genet. Genom. 2010, 37, 423–430.
  111. Bergenfelz, C.; Roxå, A.; Mehmeti, M.; Leandersson, K.; Larsson, A.-M. Clinical relevance of systemic monocytic-MDSCs in patients with metastatic breast cancer. Cancer Immunol. Immunother. 2020, 69, 435–448.
  112. Bosiljcic, M.; Cederberg, R.A.; Hamilton, M.J.; LePard, N.E.; Harbourne, B.T.; Collier, J.L.; Halvorsen, E.C.; Shi, R.; Franks, S.E.; Kim, A.Y.; et al. Targeting myeloid-derived suppressor cells in combination with primary mammary tumor resection reduces metastatic growth in the lungs. Breast Cancer Res. 2019, 21, 103.
  113. Wei, W.-C.; Lin, S.-Y.; Lan, C.-W.; Huang, Y.-C.; Lin, C.-Y.; Hsiao, P.-W.; Chen, Y.-R.; Yang, W.-C.; Yang, N.-S. Inhibiting MDSC differentiation from bone marrow with phytochemical polyacetylenes drastically impairs tumor metastasis. Sci. Rep. 2016, 6, 36663.
  114. Cao, Y.; Slaney, C.Y.; Bidwell, B.N.; Parker, B.S.; Johnstone, C.N.; Rautela, J.; Eckhardt, B.L.; Anderson, R.L. BMP4 Inhibits Breast Cancer Metastasis by Blocking Myeloid-Derived Suppressor Cell Activity. Cancer Res. 2014, 74, 5091–5102.
  115. Zhang, J.; Pang, Y.; Xie, T.; Zhu, L. CXCR4 antagonism in combination with IDO1 inhibition weakens immune suppression and inhibits tumor growth in mouse breast cancer bone metastases. OncoTargets Ther. 2019, 12, 4985–4992.
  116. Moon, E.-Y.; Ryu, Y.-K.; Lee, G.-H. Dexamethasone inhibits in vivo tumor growth by the alteration of bone marrow CD11b+ myeloid cells. Int. Immunopharmacol. 2014, 21, 494–500, Erratum in 2014, 22, 526–527.
  117. Danilin, S.; Merkel, A.; Johnson, J.R.; Johnson, R.W.; Edwards, J.R.; Sterling, J.A. Myeloid-derived suppressor cells expand during breast cancer progression and promote tumor-induced bone destruction. OncoImmunology 2012, 1, 1484–1494.
  118. Sawant, A.; Ponnazhagan, S. Myeloid-Derived Suppressor Cells as Osteoclast Progenitors: A Novel Target for Controlling Osteolytic Bone Metastasis. Cancer Res. 2013, 73, 4606–4610.
  119. Law, A.M.K.; Valdes-Mora, F.; Gallego-Ortega, D. Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer. Cells 2020, 9, 561.
  120. Sousa, S.; Määttä, J. The role of tumour-associated macrophages in bone metastasis. J. Bone Oncol. 2016, 5, 135–138.
  121. Wu, K.; Lin, K.; Li, X.; Yuan, X.; Xu, P.; Ni, P.; Xu, D. Redefining Tumor-Associated Macrophage Subpopulations and Functions in the Tumor Microenvironment. Front. Immunol. 2020, 11, 1731.
  122. Martínez, V.G.; Rubio, C.; Martínez-Fernández, M.; Segovia, C.; López-Calderón, F.; Garín, M.I.; Teijeira, A.; Munera-Maravilla, E.; Varas, A.; Sacedón, R.; et al. BMP4 Induces M2 Macrophage Polarization and Favors Tumor Progression in Bladder Cancer. Clin. Cancer Res. 2017, 23, 7388–7399.
  123. Cho, H.; Seo, Y.; Loke, K.M.; Kim, S.-W.; Oh, S.-M.; Kim, J.-H.; Soh, J.; Kim, H.S.; Lee, H.; Kim, J.; et al. Cancer-Stimulated CAFs Enhance Monocyte Differentiation and Protumoral TAM Activation via IL6 and GM-CSF Secretion. Clin. Cancer Res. 2018, 24, 5407–5421.
  124. Niu, Z.; Shi, Q.; Zhang, W.; Shu, Y.; Yang, N.; Chen, B.; Wang, Q.; Zhao, X.; Chen, J.; Cheng, N.; et al. Caspase-1 cleaves PPARγ for potentiating the pro-tumor action of TAMs. Nat. Commun. 2017, 8, 766.
  125. Buddingh, E.; Kuijjer, M.; Duim, R.A.; Bürger, H.; Agelopoulos, K.; Myklebost, O.; Serra, M.; Mertens, F.; Hogendoorn, P.; Lankester, A.C.; et al. Tumor-Infiltrating Macrophages Are Associated with Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment with Macrophage Activating Agents. Clin. Cancer Res. 2011, 17, 2110–2119.
  126. Mendoza-Reinoso, V.; McCauley, L.K.; Fournier, P.G. Contribution of Macrophages and T Cells in Skeletal Metastasis. Cancers 2020, 12, 1014.
  127. Takiguchi, S.; Korenaga, N.; Inoue, K.; Sugi, E.; Kataoka, Y.; Matsusue, K.; Futagami, K.; Li, Y.-J.; Kukita, T.; Teramoto, N.; et al. Involvement of CXCL14 in osteolytic bone metastasis from lung cancer. Int. J. Oncol. 2014, 44, 1316–1324.
  128. Hiraoka, K.; Zenmyo, M.; Watari, K.; Iguchi, H.; Fotovati, A.; Kimura, Y.N.; Hosoi, F.; Shoda, T.; Nagata, K.; Osada, H.; et al. Inhibition of bone and muscle metastases of lung cancer cells by a decrease in the number of monocytes/macrophages. Cancer Sci. 2008, 99, 1595–1602.
  129. Jones, J.; Sinder, B.; Paige, D.; Soki, F.; Koh, A.; Thiele, S.; Shiozawa, Y.; Hofbauer, L.; Daignault, S.; Roca, H.; et al. Trabectedin Reduces Skeletal Prostate Cancer Tumor Size in Association with Effects on M2 Macrophages and Efferocytosis. Neoplasia 2019, 21, 172–184.
  130. Lee, G.T.; Kwon, S.J.; Kim, J.; Kwon, Y.S.; Lee, N.; Hong, J.H.; Jamieson, C.; Kim, W.-J.; Kim, I.Y. WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages. Br. J. Cancer 2018, 118, 670–678.
  131. Jing, W.; Guo, X.; Wang, G.; Bi, Y.; Han, L.; Zhu, Q.; Qiu, C.; Tanaka, M.; Zhao, Y. Breast cancer cells promote CD169+ macrophage-associated immunosuppression through JAK2-mediated PD-L1 upregulation on macrophages. Int. Immunopharmacol. 2020, 78, 106012.
  132. Shrivastava, R.; Asif, M.; Singh, V.; Dubey, P.; Malik, S.A.; Lone, M.-U.-D.; Tewari, B.N.; Baghel, K.S.; Pal, S.; Nagar, G.K.; et al. M2 polarization of macrophages by Oncostatin M in hypoxic tumor microenvironment is mediated by mTORC2 and promotes tumor growth and metastasis. Cytokine 2019, 118, 130–143.
  133. Wu, A.C.; He, Y.; Broomfield, A.; Paatan, N.J.; Harrington, B.S.; Tseng, H.-W.; Beaven, E.A.; Kiernan, D.M.; Swindle, P.; Clubb, A.B.; et al. CD169+macrophages mediate pathological formation of woven bone in skeletal lesions of prostate cancer. J. Pathol. 2016, 239, 218–230.
  134. Jiang, P.; Gao, W.; Ma, T.; Wang, R.; Piao, Y.; Dong, X.; Wang, P.; Zhang, X.; Liu, Y.; Su, W.; et al. CD137 promotes bone metastasis of breast cancer by enhancing the migration and osteoclast differentiation of monocytes/macrophages. Theranostics 2019, 9, 2950–2966.
  135. Tourkova, I.L.; Yamabe, K.; Chatta, G.; Shurin, G.V.; Shurin, M. NK Cells Mediate Flt3 Ligand-Induced Protection of Dendritic Cell Precursors In Vivo from the Inhibition by Prostate Carcinoma in the Murine Bone Marrow Metastasis Model. J. Immunother. 2003, 26, 468–472.
  136. Imai, K.; Minamiya, Y.; Koyota, S.; Ito, M.; Saito, H.; Satoru, M.; Motoyama, S.; Sugiyama, T.; Ogawa, J.-I. Inhibition of dendritic cell migration by transforming growth factor-β1 increases tumor-draining lymph node metastasis. J. Exp. Clin. Cancer Res. 2012, 31, 3.
  137. Tanaka, H.; Shinto, O.; Yashiro, M.; Yamazoe, S.; Iwauchi, T.; Muguruma, K.; Kubo, N.; Ohira, M.; Hirakawa, K. Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity. Oncol. Rep. 2010, 24, 1637–1643.
  138. Haegel, H.; Thioudellet, C.; Hallet, R.; Geist, M.; Menguy, T.; Le Pogam, F.; Marchand, J.-B.; Toh, M.-L.; Duong, V.; Calcei, A.; et al. A unique anti-CD115 monoclonal antibody which inhibits osteolysis and skews human monocyte differentiation from M2-polarized macrophages toward dendritic cells. mAbs 2013, 5, 736–747.
  139. Kim, A.; Noh, Y.-W.; Kim, K.D.; Jang, Y.S.; Choe, Y.-K.; Lim, J.-S. Activated natural killer cell-mediated immunity is required for the inhibition of tumor metastasis by dendritic cell vaccination. Exp. Mol. Med. 2004, 36, 428–443.
  140. Liu, J.; Li, J.; Fan, Y.; Chang, K.; Yang, X.; Zhu, W.; Wu, X.; Pang, Y. Concurrent dendritic cell vaccine and strontium-89 radiation therapy in the management of multiple bone metastases. Ir. J. Med Sci. 2014, 184, 457–461.
  141. Kawano, M.; Itonaga, I.; Iwasaki, T.; Tsumura, H. Enhancement of antitumor immunity by combining anti-cytotoxic T lymphocyte antigen-4 antibodies and cryotreated tumor lysate-pulsed dendritic cells in murine osteosarcoma. Oncol. Rep. 2013, 29, 1001–1006.
  142. Morse, M.A.; Coleman, R.E.; Akabani, G.; Niehaus, N.; Coleman, D.; Lyerly, H.K. Migration of human dendritic cells after injection in patients with metastatic malignancies. Cancer Res. 1999, 59, 56–58.
  143. Bonavita, O.; Massara, M.; Bonecchi, R. Chemokine regulation of neutrophil function in tumors. Cytokine Growth Factor Rev. 2016, 30, 81–86.
  144. Massara, M.; Bonavita, O.; Savino, B.; Caronni, N.; Poeta, V.M.; Sironi, M.; Setten, E.; Recordati, C.; Crisafulli, L.; Ficara, F.; et al. ACKR2 in hematopoietic precursors as a checkpoint of neutrophil release and anti-metastatic activity. Nat. Commun. 2018, 9, 676.
  145. Jablonska, J.; Lang, S.; Sionov, R.V.; Granot, Z. The regulation of pre-metastatic niche formation by neutrophils. Oncotarget 2017, 8, 112132–112144.
  146. Engblom, C.; Pfirschke, C.; Zilionis, R.; Martins, J.D.S.; Bos, S.A.; Courties, G.; Rickelt, S.; Severe, N.; Baryawno, N.; Faget, J.; et al. Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhighneutrophils. Science 2017, 358, eaal5081.
  147. Patel, S.; Fu, S.; Mastio, J.; Dominguez, G.A.; Purohit, A.; Kossenkov, A.; Lin, C.; Alicea-Torres, K.; Sehgal, M.; Nefedova, Y.; et al. Unique pattern of neutrophil migration and function during tumor progression. Nat. Immunol. 2018, 19, 1236–1247.
  148. Wang, S.; Zhang, Z.; Fang, F.; Gao, X.; Sun, W.; Liu, H. The neutrophil/lymphocyte ratio is an independent prognostic indicator in patients with bone metastasis. Oncol. Lett. 2011, 2, 735–740.
  149. Thio, Q.C.B.S.; Goudriaan, W.A.; Janssen, S.J.; Pereira, N.R.P.; Sciubba, D.M.; Rosovksy, R.P.; Schwab, J.H. Prognostic role of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in patients with bone metastases. Br. J. Cancer 2018, 119, 737–743.
  150. Caliskan, B.; Korkmaz, A.N. Can Neutrophil/Lymphocyte Ratio be a Predictor for Bone Metastases of Solid Tumors? World J. Nucl. Med. 2016, 15, 196–199.
  151. Costanzo-Garvey, D.L.; Keeley, T.; Case, A.J.; Watson, G.F.; Alsamraae, M.; Yu, Y.; Su, K.; Heim, C.E.; Kielian, T.; Morrissey, C.; et al. Neutrophils are mediators of metastatic prostate cancer progression in bone. Cancer Immunol. Immunother. 2020, 69, 1113–1130.
  152. Győri, D.S.; Mócsai, A. Osteoclast Signal Transduction During Bone Metastasis Formation. Front. Cell Dev. Biol. 2020, 8, 507.
  153. Hofbauer, L.C.; Bozec, A.; Rauner, M.; Jakob, F.; Perner, S.; Pantel, K. Novel approaches to target the microenvironment of bone metastasis. Nat. Rev. Clin. Oncol. 2021, 1–18.
  154. Clézardin, P.; Coleman, R.; Puppo, M.; Ottewell, P.; Bonnelye, E.; Paycha, F.; Confavreux, C.B.; Holen, I. Bone metastasis: Mechanisms, therapies, and biomarkers. Physiol. Rev. 2021, 101, 797–855.
  155. Von Moos, R.; Strasser, F.; Gillessen, S.; Zaugg, K. Metastatic bone pain: Treatment options with an emphasis on bisphosphonates. Support. Care Cancer 2008, 16, 1105–1115.
  156. Jakob, T.; Tesfamariam, Y.M.; Macherey, S.; Kuhr, K.; Adams, A.; Monsef, I.; Heidenreich, A.; Skoetz, N. Bisphosphonates or RANK-ligand-inhibitors for men with prostate cancer and bone metastases: A network meta-analysis. Cochrane Database Syst. Rev. 2020, 12, CD013020.
  157. Santini, D.; Galluzzo, S.; Zoccoli, A.; Pantano, F.; Fratto, M.; Vincenzi, B.; Lombardi, L.; Gucciardino, C.; Silvestris, N.; Riva, E.; et al. New molecular targets in bone metastases. Cancer Treat. Rev. 2010, 36, S6–S10.
  158. Russell, R.G.G. Bisphosphonates: Mode of Action and Pharmacology. Pediatrics 2007, 119 (Suppl. 2), S150–S162.
  159. George, C.N.; Canuas-Landero, V.; Theodoulou, E.; Muthana, M.; Wilson, C.; Ottewell, P. Oestrogen and zoledronic acid driven changes to the bone and immune environments: Potential mechanisms underlying the differential anti-tumour effects of zoledronic acid in pre- and post-menopausal conditions. J. Bone Oncol. 2020, 25, 100317.
  160. Mariani, S.; Muraro, M.; Pantaleoni, F.; Fiore, F.; Nuschak, B.; Peola, S.; Foglietta, M.; Palumbo, A.; Coscia, M.; Castella, B.; et al. Effector γδ T cells and tumor cells as immune targets of zoledronic acid in multiple myeloma. Leukemia 2005, 19, 664–670.
  161. Veltman, J.D.; Lambers, M.E.; van Nimwegen, M.; Hendriks, R.W.; Hoogsteden, H.C.; Hegmans, J.P.; Aerts, J.G. Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma. Br. J. Cancer 2010, 103, 629–641.
  162. Tsagozis, P.; Eriksson, F.; Pisa, P. Zoledronic acid modulates antitumoral responses of prostate cancer-tumor associated macrophages. Cancer Immunol. Immunother. 2008, 57, 1451–1459.
  163. Wolf, A.M.; Rumpold, H.; Tilg, H.; Gastl, G.; Gunsilius, E.; Wolf, D. The effect of zoledronic acid on the function and differentiation of myeloid cells. Haematologica 2006, 91, 1165–1171.
  164. Fowler, D.W.; Copier, J.; Dalgleish, A.G.; Bodman-Smith, M. Zoledronic acid renders human M1 and M2 macrophages susceptible to Vδ2+ γδ T cell cytotoxicity in a perforin-dependent manner. Cancer Immunol. Immunother. 2017, 66, 1205–1215.
  165. Comito, G.; Segura, C.P.; Taddei, M.L.; Lanciotti, M.; Serni, S.; Morandi, A.; Chiarugi, P.; Giannoni, E. Zoledronic acid impairs stromal reactivity by inhibiting M2-macrophages polarization and prostate cancer-associated fibroblasts. Oncotarget 2016, 8, 118–132.
  166. Liu, H.; Wang, S.-H.; Chen, S.-C.; Chen, C.-Y.; Lin, T.-M. Zoledronic acid blocks the interaction between breast cancer cells and regulatory T-cells. BMC Cancer 2019, 19, 176.
  167. Liu, H.; Wang, S.-H.; Chen, S.-C.; Chen, C.-Y.; Lo, J.-L.; Lin, T.-M. Immune modulation of CD4+CD25+ regulatory T cells by zoledronic acid. BMC Immunol. 2016, 17, 45.
  168. Li, Y.; Du, Y.; Sun, T.; Xue, H.; Jin, Z.; Tian, J. PD-1 blockade in combination with zoledronic acid to enhance the antitumor efficacy in the breast cancer mouse model. BMC Cancer 2018, 18, 669.
  169. Sarhan, D.; Leijonhufvud, C.; Murray, S.; Witt, K.; Seitz, C.; Wallerius, M.; Xie, H.; Ullén, A.; Harmenberg, U.; Lidbrink, E.; et al. Zoledronic acid inhibits NFAT and IL-2 signaling pathways in regulatory T cells and diminishes their suppressive function in patients with metastatic cancer. OncoImmunology 2017, 6, e1338238.
  170. Ubellacker, J.M.; Baryawno, N.; Severe, N.; DeCristo, M.J.; Sceneay, J.; Hutchinson, J.N.; Haider, M.-T.; Rhee, C.S.; Qin, Y.; Gregory, W.M.; et al. Modulating Bone Marrow Hematopoietic Lineage Potential to Prevent Bone Metastasis in Breast Cancer. Cancer Res. 2018, 78, 5300–5314.
  171. Zysk, A.; DeNichilo, M.O.; Panagopoulos, V.; Zinonos, I.; Liapis, V.; Hay, S.; Ingman, W.; Ponomarev, V.; Atkins, G.; Findlay, D.; et al. Adoptive transfer of ex vivo expanded Vγ9Vδ2 T cells in combination with zoledronic acid inhibits cancer growth and limits osteolysis in a murine model of osteolytic breast cancer. Cancer Lett. 2017, 386, 141–150.
  172. Nicol, A.J.; Tokuyama, H.; Mattarollo, S.R.; Hagi, T.; Suzuki, K.; Yokokawa, K.; Nieda, M. Clinical evaluation of autologous gamma delta T cell-based immunotherapy for metastatic solid tumours. Br. J. Cancer 2011, 105, 778–786.
  173. Noguchi, A.; Kaneko, T.; Kamigaki, T.; Fujimoto, K.; Ozawa, M.; Saito, M.; Ariyoshi, N.; Goto, S. Zoledronate-activated Vγ9γδ T cell-based immunotherapy is feasible and restores the impairment of γδ T cells in patients with solid tumors. Cytotherapy 2011, 13, 92–97.
  174. Lang, J.M.; Kaikobad, M.R.; Wallace, M.; Staab, M.J.; Horvath, D.L.; Wilding, G.; Liu, G.; Eickhoff, J.C.; McNeel, D.G.; Malkovsky, M. Pilot trial of interleukin-2 and zoledronic acid to augment γδ T cells as treatment for patients with refractory renal cell carcinoma. Cancer Immunol. Immunother. 2011, 60, 1447–1460.
  175. Meraviglia, S.; Eberl, M.; Vermijlen, D.; Todaro, M.; Buccheri, S.; Cicero, G.; La Mendola, C.; Guggino, G.; D’Asaro, M.; Orlando, V.; et al. In vivo manipulation of Vγ9Vδ2 T cells with zoledronate and low-dose interleukin-2 for immunotherapy of advanced breast cancer patients. Clin. Exp. Immunol. 2010, 161, 290–297.
  176. Dieli, F.; Vermijlen, D.; Fulfaro, F.; Caccamo, N.; Meraviglia, S.; Cicero, G.; Roberts, A.W.; Buccheri, S.; D’Asaro, M.; Gebbia, N.; et al. Targeting Human γδ T Cells with Zoledronate and Interleukin-2 for Immunotherapy of Hormone-Refractory Prostate Cancer. Cancer Res. 2007, 67, 7450–7457.
  177. Nagamine, I.; Yamaguchi, Y.; Ohara, M.; Ikeda, T.; Okada, M. Induction of gamma delta T cells using zoledronate plus interleukin-2 in patients with metastatic cancer. Hiroshima J. Med Sci. 2009, 58, 37–44.
  178. Smith, H.A.; Kang, Y. The metastasis-promoting roles of tumor-associated immune cells. J. Mol. Med. 2013, 91, 411–429.
  179. De Groot, A.; Appelman-Dijkstra, N.; van der Burg, S.; Kroep, J. The anti-tumor effect of RANKL inhibition in malignant solid tumors—A systematic review. Cancer Treat. Rev. 2018, 62, 18–28.
  180. Ahern, E.; Smyth, M.J.; Dougall, W.C.; Teng, M.W.L. Roles of the RANKL–RANK axis in antitumour immunity—Implications for therapy. Nat. Rev. Clin. Oncol. 2018, 15, 676–693.
  181. Van Dam, P.A.; Verhoeven, Y.; Trinh, X.B.; Wouters, A.; Lardon, F.; Prenen, H.; Smits, E.; Baldewijns, M.; Lammens, M. RANK/RANKL signaling inhibition may improve the effectiveness of checkpoint blockade in cancer treatment. Crit. Rev. Oncol. 2019, 133, 85–91.
  182. Smyth, M.; Yagita, H.; McArthur, G.A. Combination Anti-CTLA-4 and Anti-RANKL in Metastatic Melanoma. J. Clin. Oncol. 2016, 34, e104–e106.
  183. Angela, Y.; Haferkamp, S.; Weishaupt, C.; Ugurel, S.; Becker, J.C.; Oberndörfer, F.; Alar, V.; Satzger, I.; Gutzmer, R. Combination of denosumab and immune checkpoint inhibition: Experience in 29 patients with metastatic melanoma and bone metastases. Cancer Immunol. Immunother. 2019, 68, 1187–1194.
  184. Afzal, M.Z.; Shirai, K. Immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy alone versus immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy in combination with anti-RANKL denosumuab in malignant melanoma: A retrospective analysis at a tertiary care center. Melanoma Res. 2018, 28, 341–347.
  185. Ahern, E.; Harjunpää, H.; O’Donnell, J.S.; Allen, S.; Dougall, W.C.; Teng, M.W.L.; Smyth, M.J. RANKL blockade improves efficacy of PD1-PD-L1 blockade or dual PD1-PD-L1 and CTLA4 blockade in mouse models of cancer. OncoImmunology 2018, 7, e1431088.
  186. Simatou, A.; Sarantis, P.; Koustas, E.; Papavassiliou, A.G.; Karamouzis, M.V. The Role of the RANKL/RANK Axis in the Prevention and Treatment of Breast Cancer with Immune Checkpoint Inhibitors and Anti-RANKL. Int. J. Mol. Sci. 2020, 21, 7570.
  187. Gallicchio, R.; Mastrangelo, P.A.; Nardelli, A.; Mainenti, P.P.; Colasurdo, A.P.; Landriscina, M.; Guglielmi, G.; Storto, G. Radium-223 for the treatment of bone metastases in castration-resistant prostate cancer: When and why. Tumori J. 2019, 105, 367–377.
  188. ASCO GU 2021: Randomized Phase II Study Evaluating the Addition of Pembrolizumab to Radium-223 in Metastatic Castration-Resistant Prostate Cancer. Available online: (accessed on 13 April 2021).
  189. Kim, J.W.; Shin, M.S.; Kang, Y.; Kang, I.; Petrylak, D.P. Immune Analysis of Radium-223 in Patients With Metastatic Prostate Cancer. Clin. Genitourin. Cancer 2018, 16, e469–e476.
  190. Giles, A.J.; Hutchinson, M.-K.N.D.; Sonnemann, H.M.; Jung, J.; Fecci, P.E.; Ratnam, N.M.; Zhang, W.; Song, H.; Bailey, R.; Davis, D.; et al. Dexamethasone-induced immunosuppression: Mechanisms and implications for immunotherapy. J. Immunother. Cancer 2018, 6, 51.
  191. Marshall, C.H.; Fu, W.; Wang, H.; Park, J.C.; DeWeese, T.L.; Tran, P.T.; Song, D.Y.; King, S.; Afful, M.; Hurrelbrink, J.; et al. Randomized Phase II Trial of Sipuleucel-T with or without Radium-223 in Men with Bone-metastatic Castration-resistant Prostate Cancer. Clin. Cancer Res. 2021, 27, 1623–1630.
  192. O’Sullivan, J.M.; Carles, J.; Cathomas, R.; Gomez-Iturriaga, A.; Heinrich, D.; Kramer, G.; Ost, P.; Van Oort, I.; Tombal, B. Radium-223 Within the Evolving Treatment Options for Metastatic Castration-resistant Prostate Cancer: Recommendations from a European Expert Working Group. Eur. Urol. Oncol. 2020, 3, 455–463.
  193. Kähkönen, T.E.; Halleen, J.M.; Bernoulli, J. Limited data from clinical trials assessing immunotherapy effects on bone metastases. Cancer Res. 2021, in press.
  194. Schmid, P.; Rugo, H.S.; Adams, S.; Schneeweiss, A.; Barrios, C.H.; Iwata, H.; Diéras, V.; Henschel, V.; Molinero, L.; Chui, S.Y.; et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): Updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020, 21, 44–59.
  195. Moseley, K.F.; Naidoo, J.; Bingham, C.O.; Carducci, M.A.; Forde, P.M.; Gibney, G.T.; Lipson, E.J.; Shah, A.A.; Sharfman, W.H.; Cappelli, L.C. Immune-related adverse events with immune checkpoint inhibitors affecting the skeleton: A seminal case series. J. Immunother. Cancer 2018, 6, 104.
  196. Hilal, T.; Bansal, P.; Kelemen, K.; Slack, J. Nivolumab-associated bone marrow necrosis. Ann. Oncol. 2018, 29, 513–514.
  197. Heidegger, I.; Necchi, A.; Pircher, A.; Tsaur, I.; Marra, G.; Kasivisvanathan, V.; Kretschmer, A.; Mathieu, R.; Ceci, F.; Bergh, R.C.V.D.; et al. A Systematic Review of the Emerging Role of Immune Checkpoint Inhibitors in Metastatic Castration-resistant Prostate Cancer: Will Combination Strategies Improve Efficacy? Eur. Urol. Oncol. 2020.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Feedback