Cancer Immunology, Immunotherapy

, Volume 65, Issue 7, pp 835–845 | Cite as

Adoptive transfer of osteoclast-expanded natural killer cells for immunotherapy targeting cancer stem-like cells in humanized mice

  • Anna K. Kozlowska
  • Kawaljit Kaur
  • Paytsar Topchyan
  • Anahid Jewett
Focussed Research Review


Based on data obtained from oral, pancreatic and lung cancers, glioblastoma, and melanoma, we have established that natural killer (NK) cells target cancer stem-like cells (CSCs). CSCs displaying low MHC class I, CD54, and PD-L1 are killed by cytotoxic NK cells and are differentiated by split anergized NK cells through both membrane bound and secreted forms of TNF-α and IFN-γ. NK cells select and differentiate both healthy and transformed stem-like cells, resulting in target cell maturation and shaping of their microenvironment. In our recent studies, we have observed that oral, pancreatic, and melanoma CSCs were capable of forming large tumors in humanized bone marrow, liver, thymus (hu-BLT) mice with fully reconstituted human immune system. In addition, major human immune subsets including NK cells, T cells, B cells, and monocytes were present in the spleen, bone marrow, peripheral blood, and tumor microenvironment. Similar to our previously published in vitro data, CSCs differentiated with split anergized NK cells prior to implantation in mice formed smaller tumors. Intravenous injection of functionally potent osteoclast-expanded NK cells inhibited tumor growth through differentiation of CSCs in humanized mice. In this review, we present current approaches, advances, and existing limitations in studying interactions of the immune system with the tumor, in particular NK cells with CSCs, using in vivo preclinical hu-BLT mouse model. In addition, we discuss the use of osteoclast-expanded NK cells in targeting cancer stem-like tumors in humanized mice—a strategy that provides a much-needed platform to develop effective cancer immunotherapies.


Osteoclast-expanded NK cells Cancer immunotherapy BLT humanized mice CSCs CITIM 2015 



Cluster of differentiation


Cancer stem-like cell


Dendritic cell


Human cord blood


Human histocompatibility leukocyte antigen


Hematopoietic stem cell


Humanized tumor mice


Bone marrow, liver, thymus humanized mice






Interleukin 2 receptor subunit gamma


Mouse erythroleukemia cell line


Major histocompatibility complex

NK cell

Natural killer cell


Non-obese diabetic


NOD-scid IL2RGnull


Oral squamous cancer stem cell


Programmed death-ligand 1 (also known as B7H1)


Patient-derived xenografts


Paul Karl Horan fluorescent dye


Polyinosinic/polycytidylic acid


Severe combined immunodeficiency


Tumor necrosis factor



Anna K. Kozlowska was supported by the Polish Ministry of Sciences and Higher Education and Mobility Plus award.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.


  1. 1.
    Tseng H-C, Arasteh A, Paranjpe A, Teruel A, Yang W, Behel A, Alva JA, Walter G, Head C, Ishikawa T, Herschman HR, Cacalano N, Pyle AD, Park N-H, Jewett A (2010) Increased lysis of stem cells but not their differentiated cells by Natural Killer cells; de-differentiation or reprogramming activates NK cells. PLoS ONE. doi: 10.1371/journal.pone.0011590 Google Scholar
  2. 2.
    Jewett A, Man Y-G, Tseng H-C (2013) Dual functions of Natural Killer cells in selection and differentiation of stem cells; role in regulation of inflammation and regeneration of tissues. J Cancer 4(1):12–24. doi: 10.7150/jca.5519 CrossRefPubMedGoogle Scholar
  3. 3.
    Ames E, Canter RJ, Grossenbacher SK, Mac S, Chen M, Smith RC, Hagino T, Perez-Cunningham J, Sckisel GD, Urayama S, Monjazeb AM, Fragoso RC, Sayers TJ, Murphy WJ (2015) NK cells preferentially target tumor cells with a cancer stem cell phenotype. J Immunol 195(8):4010–4019. doi: 10.4049/jimmunol.1500447 CrossRefPubMedGoogle Scholar
  4. 4.
    Jewett A, Cavalcanti M, Bonavida B (1997) Pivotal role of endogenous TNF-alpha in the induction of functional inactivation and apoptosis in NK cells. J Immunol 159(10):4815–4822PubMedGoogle Scholar
  5. 5.
    Jewett A, Bonavida B (1995) Target-induced anergy of Natural Killer cytotoxic function is restricted to the NK-target conjugate subset. Cell Immunol 160(1):91–97CrossRefPubMedGoogle Scholar
  6. 6.
    Jewett A, Bonavida B (2000) MHC-Class I antigens regulate both the function and the survival of human peripheral blood NK cells: role of endogenously secreted TNF-alpha. Clin Immunol 96(1):19–28CrossRefPubMedGoogle Scholar
  7. 7.
    Jewett A, Cacalano NA, Head C, Teruel A (2006) Coengagement of CD16 and CD94 receptors mediates secretion of chemokines and induces apoptotic death of naive Natural Killer cells. Clin Cancer Res 12(7 Pt 1):1994–2003CrossRefPubMedGoogle Scholar
  8. 8.
    Jewett A, Teruel A, Romero M, Head C, Cacalano N (2008) Rapid and potent induction of cell death and loss of NK cell cytotoxicity against oral tumors by F(ab’)2 fragment of anti-CD16 antibody. Cancer Immunol Immunother: CII 57(7):1053–1066CrossRefPubMedGoogle Scholar
  9. 9.
    Jewett A, Bonavida B (1996) Target-induced inactivation and cell death by apoptosis in a subset of human NK cells. J Immunol 156(3):907–915PubMedGoogle Scholar
  10. 10.
    Tseng H-C, Bui V, Man Y-G, Cacalano N, Jewett A (2014) Induction of split anergy conditions Natural Killer cells to promote differentiation of stem cells through cell–cell contact and secreted factors. Front Immunol 5:269. doi: 10.3389/fimmu.2014.00269 PubMedPubMedCentralGoogle Scholar
  11. 11.
    Tseng HC, Cacalano N, Jewett A (2015) Split anergized Natural Killer cells halt inflammation by inducing stem cell differentiation, resistance to NK cell cytotoxicity and prevention of cytokine and chemokine secretion. Oncotarget 6(11):8947–8959CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172(5):2731–2738CrossRefPubMedGoogle Scholar
  13. 13.
    Rongvaux A, Takizawa H, Strowig T, Willinger T, Eynon EE, Flavell RA, Manz MG (2013) Human hemato-lymphoid system mice: current use and future potential for medicine. Annu Rev Immunol 31:635–674. doi: 10.1146/annurev-immunol-032712-095921 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human Natural Killer-cell subsets. Trends Immunol 22(11):633–640CrossRefPubMedGoogle Scholar
  15. 15.
    Yokoyama WM, Kim S, French AR (2004) The dynamic life of Natural Killer cells. Annu Rev Immunol 22:405–429. doi: 10.1146/annurev.immunol.22.012703.104711 CrossRefPubMedGoogle Scholar
  16. 16.
    Yoshizawa K, Nakajima S, Notake T, Miyagawa S, Hida S, Taki S (2011) IL-15-high-responder developing NK cells bearing Ly49 receptors in IL-15 −/− mice. J Immunol 187(10):5162–5169. doi: 10.4049/jimmunol.1101561 CrossRefPubMedGoogle Scholar
  17. 17.
    Tseng HC, Arasteh A, Kaur K, Kozlowska A, Topchyan P, Jewett A (2015) Differential cytotoxicity but augmented IFN-gamma secretion by NK cells after interaction with monocytes from humans, and those from wild type and myeloid-specific COX-2 knockout mice. Front Immunol 6:259. doi: 10.3389/fimmu.2015.00259 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Bosma GC, Custer RP, Bosma MJ (1983) A severe combined immunodeficiency mutation in the mouse. Nature 301(5900):527–530CrossRefPubMedGoogle Scholar
  19. 19.
    Isaacson JH, Cattanach BM (1962) [Report]. Mouse News Lett 27:31Google Scholar
  20. 20.
    Levy EM, Yonkosky D, Schmid K, Cooperband SR (1977) Enrichment of the murine Natural Killer (NK) and mitogen induced cellular cytotoxicity (MICC) cells using preparative free-flow high voltage electrophoresis. Prep Biochem 7(6):467–478. doi: 10.1080/00327487708065514 PubMedGoogle Scholar
  21. 21.
    Nomura T, Watanabe T, Habu S (2008) Humanized mice. Preface. Curr Top Microbiol Immunol 324:v–viPubMedGoogle Scholar
  22. 22.
    Phillips RA, Jewett MA, Gallie BL (1989) Growth of human tumors in immune-deficient scid mice and nude mice. Curr Top Microbiol Immunol 152:259–263PubMedGoogle Scholar
  23. 23.
    Kataoka S, Satoh J, Fujiya H, Toyota T, Suzuki R, Itoh K, Kumagai K (1983) Immunologic aspects of the nonobese diabetic (NOD) mouse. Abnormalities of cellular immunity. Diabetes 32(3):247–253CrossRefPubMedGoogle Scholar
  24. 24.
    Shultz LD, Schweitzer PA, Christianson SW, Gott B, Schweitzer IB, Tennent B, McKenna S, Mobraaten L, Rajan TV, Greiner DL et al (1995) Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol 154(1):180–191PubMedGoogle Scholar
  25. 25.
    Baxter AG, Cooke A (1993) Complement lytic activity has no role in the pathogenesis of autoimmune diabetes in NOD mice. Diabetes 42(11):1574–1578CrossRefPubMedGoogle Scholar
  26. 26.
    Greiner DL, Hesselton RA, Shultz LD (1998) SCID mouse models of human stem cell engraftment. Stem Cells 16(3):166–177. doi: 10.1002/stem.160166 CrossRefPubMedGoogle Scholar
  27. 27.
    Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, Kotb M, Gillies SD, King M, Mangada J, Greiner DL, Handgretinger R (2005) Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol 174(10):6477–6489CrossRefPubMedGoogle Scholar
  28. 28.
    Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL (2012) Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol 12(11):786–798. doi: 10.1038/nri3311 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G, Watanabe T, Akashi K, Shultz LD, Harada M (2005) Development of functional human blood and immune systems in NOD/SCID/IL2 receptor gamma chain(null) mice. Blood 106(5):1565–1573. doi: 10.1182/blood-2005-02-0516 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Shultz LD, Ishikawa F, Greiner DL (2007) Humanized mice in translational biomedical research. Nat Rev Immunol 7(2):118–130. doi: 10.1038/nri2017 CrossRefPubMedGoogle Scholar
  31. 31.
    Ito A, Ishida T, Yano H, Inagaki A, Suzuki S, Sato F, Takino H, Mori F, Ri M, Kusumoto S, Komatsu H, Iida S, Inagaki H, Ueda R (2009) Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rgamma(null) mouse model. Cancer Immunol Immunother 58(8):1195–1206. doi: 10.1007/s00262-008-0632-0 CrossRefPubMedGoogle Scholar
  32. 32.
    King MA, Covassin L, Brehm MA, Racki W, Pearson T, Leif J, Laning J, Fodor W, Foreman O, Burzenski L, Chase TH, Gott B, Rossini AA, Bortell R, Shultz LD, Greiner DL (2009) Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex. Clin Exp Immunol 157(1):104–118. doi: 10.1111/j.1365-2249.2009.03933.x CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Shimizu S, Hong P, Arumugam B, Pokomo L, Boyer J, Koizumi N, Kittipongdaja P, Chen A, Bristol G, Galic Z, Zack JA, Yang O, Chen IS, Lee B, An DS (2010) A highly efficient short hairpin RNA potently down-regulates CCR5 expression in systemic lymphoid organs in the hu-BLT mouse model. Blood 115(8):1534–1544. doi: 10.1182/blood-2009-04-215855 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Vatakis DN, Bristol GC, Kim SG, Levin B, Liu W, Radu CG, Kitchen SG, Zack JA (2012) Using the BLT humanized mouse as a stem cell based gene therapy tumor model. J Vis Exp 70:e4181. doi: 10.3791/4181 PubMedGoogle Scholar
  35. 35.
    Stoddart CA, Maidji E, Galkina SA, Kosikova G, Rivera JM, Moreno ME, Sloan B, Joshi P, Long BR (2011) Superior human leukocyte reconstitution and susceptibility to vaginal HIV transmission in humanized NOD-scid IL-2Rgamma(−/−) (NSG) BLT mice. Virology 417(1):154–160. doi: 10.1016/j.virol.2011.05.013 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti JC, Lanzavecchia A, Manz MG (2004) Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 304(5667):104–107. doi: 10.1126/science.1093933 CrossRefPubMedGoogle Scholar
  37. 37.
    Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, Ueyama Y, Koyanagi Y, Sugamura K, Tsuji K, Heike T, Nakahata T (2002) NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood 100(9):3175–3182. doi: 10.1182/blood-2001-12-0207 CrossRefPubMedGoogle Scholar
  38. 38.
    Strowig T, Chijioke O, Carrega P, Arrey F, Meixlsperger S, Rämer PC, Ferlazzo G, Münz C (2010) Human NK cells of mice with reconstituted human immune system components require preactivation to acquire functional competence. Blood 116(20):4158–4167. doi: 10.1182/blood-2010-02-270678 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Olesen R, Wahl A, Denton PW, Garcia JV (2011) Immune reconstitution of the female reproductive tract of humanized BLT mice and their susceptibility to human immunodeficiency virus infection. J Reprod Immunol 88(2):195–203. doi: 10.1016/j.jri.2010.11.005 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Denton PW, Olesen R, Choudhary SK, Archin NM, Wahl A, Swanson MD, Chateau M, Nochi T, Krisko JF, Spagnuolo RA, Margolis DM, Garcia JV (2012) Generation of HIV latency in humanized BLT mice. J Virol 86(1):630–634. doi: 10.1128/JVI.06120-11 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Manz MG (2007) Human-hemato-lymphoid-system mice: opportunities and challenges. Immunity 26(5):537–541. doi: 10.1016/j.immuni.2007.05.001 CrossRefPubMedGoogle Scholar
  42. 42.
    Vatakis DN, Koya RC, Nixon CC, Wei L, Kim SG, Avancena P, Bristol G, Baltimore D, Kohn DB, Ribas A, Radu CG, Galic Z, Zack JA (2011) Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells. Proc Natl Acad Sci USA 108(51):E1408–E1416. doi: 10.1073/pnas.1115050108 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Kwant-Mitchell A, Pek EA, Rosenthal KL, Ashkar AA (2009) Development of functional human NK cells in an immunodeficient mouse model with the ability to provide protection against tumor challenge. PLoS ONE 4(12):e8379. doi: 10.1371/journal.pone.0008379 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Pek EA, Chan T, Reid S, Ashkar AA (2011) Characterization and IL-15 dependence of NK cells in humanized mice. Immunobiology 216(1–2):218–224. doi: 10.1016/j.imbio.2010.04.008 CrossRefPubMedGoogle Scholar
  45. 45.
    Chen Q, Khoury M, Chen J (2009) Expression of human cytokines dramatically improves reconstitution of specific human-blood lineage cells in humanized mice. Proc Natl Acad Sci USA 106(51):21783–21788. doi: 10.1073/pnas.0912274106 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Huntington ND, Legrand N, Alves NL, Jaron B, Weijer K, Plet A, Corcuff E, Mortier E, Jacques Y, Spits H, Di Santo JP (2009) IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J Exp Med 206(1):25–34. doi: 10.1084/jem.20082013 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Andre MC, Erbacher A, Gille C, Schmauke V, Goecke B, Hohberger A, Mang P, Wilhelm A, Mueller I, Herr W, Lang P, Handgretinger R, Hartwig UF (2010) Long-term human CD34+ stem cell-engrafted nonobese diabetic/SCID/IL-2R gamma(null) mice show impaired CD8+ T cell maintenance and a functional arrest of immature NK cells. J Immunol 185(5):2710–2720. doi: 10.4049/jimmunol.1000583 CrossRefPubMedGoogle Scholar
  48. 48.
    Mrozek E, Anderson P, Caligiuri MA (1996) Role of interleukin-15 in the development of human CD56+ Natural Killer cells from CD34+ hematopoietic progenitor cells. Blood 87(7):2632–2640PubMedGoogle Scholar
  49. 49.
    Sato T, Laver JH, Aiba Y, Ogawa M (1999) NK cell colony formation from human fetal thymocytes. Exp Hematol 27(4):726–733CrossRefPubMedGoogle Scholar
  50. 50.
    Vosshenrich CA, Ranson T, Samson SI, Corcuff E, Colucci F, Rosmaraki EE, Di Santo JP (2005) Roles for common cytokine receptor gamma-chain-dependent cytokines in the generation, differentiation, and maturation of NK cell precursors and peripheral NK cells in vivo. J Immunol 174(3):1213–1221CrossRefPubMedGoogle Scholar
  51. 51.
    Fischer A, Le Deist F, Hacein-Bey-Abina S, Andre-Schmutz I, Basile Gde S, de Villartay JP, Cavazzana-Calvo M (2005) Severe combined immunodeficiency. A model disease for molecular immunology and therapy. Immunol Rev 203:98–109. doi: 10.1111/j.0105-2896.2005.00223.x CrossRefPubMedGoogle Scholar
  52. 52.
    Ferlazzo G, Pack M, Thomas D, Paludan C, Schmid D, Strowig T, Bougras G, Muller WA, Moretta L, Munz C (2004) Distinct roles of IL-12 and IL-15 in human Natural Killer cell activation by dendritic cells from secondary lymphoid organs. Proc Natl Acad Sci USA 101(47):16606–16611. doi: 10.1073/pnas.0407522101 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Strowig T, Chijioke O, Carrega P, Arrey F, Meixlsperger S, Ramer PC, Ferlazzo G, Munz C (2010) Human NK cells of mice with reconstituted human immune system components require preactivation to acquire functional competence. Blood 116(20):4158–4167. doi: 10.1182/blood-2010-02-270678 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Wege AK, Ernst W, Eckl J, Frankenberger B, Vollmann-Zwerenz A, Männel DN, Ortmann O, Kroemer A, Brockhoff G (2011) Humanized tumor mice—a new model to study and manipulate the immune response in advanced cancer therapy. Int J Cancer 129(9):2194–2206. doi: 10.1002/ijc.26159 CrossRefPubMedGoogle Scholar
  55. 55.
    Shurin MR, Umansky V, Malyguine A, Hurwitz AA, Apte RN, Whiteside T, Jewett A, Thanavala Y, Murphy WJ (2014) Cellular and molecular pathways in the tumor immunoenvironment: 3rd Cancer Immunotherapy and Immunomonitoring (CITIM) meeting, 22–25 April 2013, Krakow, Poland. Cancer Immunol Immunother 63(1):73–80. doi: 10.1007/s00262-013-1501-z CrossRefPubMedGoogle Scholar
  56. 56.
    Raulet DH, Guerra N (2009) Oncogenic stress sensed by the immune system: role of Natural Killer cell receptors. Nat Rev Immunol 9(8):568–580. doi: 10.1038/nri2604 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Pietra G, Manzini C, Rivara S, Vitale M, Cantoni C, Petretto A, Balsamo M, Conte R, Benelli R, Minghelli S, Solari N, Gualco M, Queirolo P, Moretta L, Mingari MC (2012) Melanoma cells inhibit Natural Killer cell function by modulating the expression of activating receptors and cytolytic activity. Cancer Res 72(6):1407–1415. doi: 10.1158/0008-5472.CAN-11-2544 CrossRefPubMedGoogle Scholar
  58. 58.
    Garcia-Iglesias T, Del Toro-Arreola A, Albarran-Somoza B, Del Toro-Arreola S, Sanchez-Hernandez PE, Ramirez-Duenas MG, Balderas-Pena LM, Bravo-Cuellar A, Ortiz-Lazareno PC, Daneri-Navarro A (2009) Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions. BMC Cancer 9:186. doi: 10.1186/1471-2407-9-186 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Peng YP, Zhang JJ, Liang WB, Tu M, Lu ZP, Wei JS, Jiang KR, Gao WT, Wu JL, Xu ZK, Miao Y, Zhu Y (2014) Elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates Natural Killer cell dysfunction. BMC Cancer 14:738. doi: 10.1186/1471-2407-14-738 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Mamessier E, Sylvain A, Bertucci F, Castellano R, Finetti P, Houvenaeghel G, Charaffe-Jaufret E, Birnbaum D, Moretta A, Olive D (2011) Human breast tumor cells induce self-tolerance mechanisms to avoid NKG2D-mediated and DNAM-mediated NK cell recognition. Cancer Res 71(21):6621–6632. doi: 10.1158/0008-5472.CAN-11-0792 CrossRefPubMedGoogle Scholar
  61. 61.
    Chen Z, Malhotra PS, Thomas GR, Ondrey FG, Duffey DC, Smith CW, Enamorado I, Yeh NT, Kroog GS, Rudy S, McCullagh L, Mousa S, Quezado M, Herscher LL, Van Waes C (1999) Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res 5(6):1369–1379PubMedGoogle Scholar
  62. 62.
    Tseng HC, Kanayama K, Kaur K, Park SH, Park S, Kozlowska A, Sun S, McKenna CE, Nishimura I, Jewett A (2015) Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: role in osteoclast-mediated NK cell activation. Oncotarget 6(24):20002–20025CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Cooper MA, Elliott JM, Keyel PA, Yang L, Carrero JA, Yokoyama WM (2009) Cytokine-induced memory-like Natural Killer cells. Proc Natl Acad Sci USA 106(6):1915–1919. doi: 10.1073/pnas.0813192106 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Kelland LR (2004) Of mice and men: values and liabilities of the athymic nude mouse model in anticancer drug development. Eur J Cancer 40(6):827–836. doi: 10.1016/j.ejca.2003.11.028 CrossRefPubMedGoogle Scholar
  65. 65.
    Nonoyama S, Smith FO, Bernstein ID, Ochs HD (1993) Strain-dependent leakiness of mice with severe combined immune deficiency. J Immunol 150(9):3817–3824PubMedGoogle Scholar
  66. 66.
    Shultz LD, Goodwin N, Ishikawa F, Hosur V, Lyons BL, Greiner DL (2014) Human cancer growth and therapy in immunodeficient mouse models. Cold Spring Harb Protoc 7:694–708. doi: 10.1101/pdb.top073585 Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Anna K. Kozlowska
    • 1
    • 3
  • Kawaljit Kaur
    • 1
  • Paytsar Topchyan
    • 1
  • Anahid Jewett
    • 1
    • 2
  1. 1.Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive BiotechnologyUCLALos AngelesUSA
  2. 2.The Jonsson Comprehensive Cancer CenterUCLA School of Dentistry and MedicineLos AngelesUSA
  3. 3.Department of Tumor Immunology, Chair of Medical BiotechnologyPoznan University of Medical SciencesPoznanPoland

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