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Stem cells-derived natural killer cells for cancer immunotherapy: current protocols, feasibility, and benefits of ex vivo generated natural killer cells in treatment of advanced solid tumors

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Abstract

Nowadays, natural killer (NK) cell-based immunotherapy provides a practical therapeutic strategy for patients with advanced solid tumors (STs). This approach is adaptively conducted by the autologous and identical NK cells after in vitro expansion and overnight activation. However, the NK cell-based cancer immunotherapy has been faced with some fundamental and technical limitations. Moreover, the desirable outcomes of the NK cell therapy may not be achieved due to the complex tumor microenvironment by inhibition of intra-tumoral polarization and cytotoxicity of implanted NK cells. Currently, stem cells (SCs) technology provides a powerful opportunity to generate more effective and universal sources of the NK cells. Till now, several strategies have been developed to differentiate types of the pluripotent and adult SCs into the mature NK cells, with both feeder layer-dependent and/or feeder laye-free strategies. Higher cytokine production and intra-tumoral polarization capabilities as well as stronger anti-tumor properties are the main features of these SCs-derived NK cells. The present review article focuses on the principal barriers through the conventional NK cell immunotherapies for patients with advanced STs. It also provides a comprehensive resource of protocols regarding the generation of SCs-derived NK cells in an ex vivo condition.

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References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    Google Scholar 

  2. Shaked Y (2019) The pro-tumorigenic host response to cancer therapies. Nat Rev Cancer 19:667–685

    CAS  PubMed  Google Scholar 

  3. Gavhane Y, Shete A, Bhagat A, Shinde V, Bhong K, Khairnar G, Yadav A (2011) Solid tumors: facts, challenges and solutions. Int J Pharm Sci Res 2:1–12

    Google Scholar 

  4. Luke JJ, Lemons JM, Karrison TG et al (2018) Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol 36:1611

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Veluchamy JP, Lopez-Lastra S, Spanholtz J et al (2017) In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. Front Immunol 8:87

    PubMed  PubMed Central  Google Scholar 

  6. Restifo NP, Smyth MJ, Snyder A (2016) Acquired resistance to immunotherapy and future challenges. Nat Rev Cancer 16:121

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Mohsenikia M, Farhangi B, Alizadeh AM et al (2016) Therapeutic effects of dendrosomal solanine on a metastatic breast tumor. Life Sci 148:260–267

    CAS  PubMed  Google Scholar 

  8. Dupuis F, Lamant L, Gerard E et al (2018) Clinical, histological and molecular predictors of metastatic melanoma responses to anti-PD-1 immunotherapy. Br J Cancer 119:193–199

    PubMed  PubMed Central  Google Scholar 

  9. Somasundaram R, Zhang G, Fukunaga-Kalabis M et al (2017) Tumor-associated B-cells induce tumor heterogeneity and therapy resistance. Nat Commun 8:1–16

    Google Scholar 

  10. Shiri S, Alizadeh AM, Baradaran B, Farhanghi B, Shanehbandi D, Khodayari S, Khodayari H, Tavassoli A (2015) Dendrosomal curcumin suppresses metastatic breast cancer in mice by changing m1/m2 macrophage balance in the tumor microenvironment. Asian Pac J Cancer Prev 16:3917–3922

    PubMed  Google Scholar 

  11. Farhanji B, Latifpour M, Alizadeh AM, Khodayari H, Khodayari S, Khaniki M, Ghasempour S (2015) Tumor suppression effects of myoepithelial cells on mice breast cancer. Eur J Pharmacol 765:171–178

    CAS  PubMed  Google Scholar 

  12. Krause SW, Gastpar R, Andreesen R, Gross C, Ullrich H, Thonigs G, Pfister K, Multhoff G (2004) Treatment of colon and lung cancer patients with ex vivo heat shock protein 70-peptide-activated, autologous natural killer cells: a clinical phase I trial. Clin Cancer Res 10:3699–3707

    CAS  PubMed  Google Scholar 

  13. Hermanson DL, Bendzick L, Pribyl L, McCullar V, Vogel RI, Miller JS, Geller MA, Kaufman DS (2016) Induced pluripotent stem cell-derived natural killer cells for treatment of ovarian cancer. St Cells 34:93–101

    CAS  Google Scholar 

  14. Koepsell SA, Miller JS, McKenna DH Jr (2013) Natural killer cells: a review of manufacturing and clinical utility. Transfusion 53:404–410

    CAS  PubMed  Google Scholar 

  15. Hoogstad-van Evert JS, Cany J, van den Brand D et al (2017) Umbilical cord blood CD34+ progenitor-derived NK cells efficiently kill ovarian cancer spheroids and intraperitoneal tumors in NOD/SCID/IL2Rgnull mice. Oncoimmunology 6:e1320630

    PubMed  PubMed Central  Google Scholar 

  16. Zeng J, Tang SY, Toh LL, Wang S (2017) Generation of “off-the-shelf” natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. St Cell Rep 9:1796–1812

    CAS  Google Scholar 

  17. Bjordahl R, Mahmood S, Gaidarova S et al (2018) FT500, an off-the-shelf NK cell cancer immunotherapy derived from a master pluripotent cell line, enhances T-cell activation and recruitment to overcome checkpoint blockade resistance. AACR. https://doi.org/10.1158/1538-7445.AM2018-3576

    Article  Google Scholar 

  18. O’Brien KL, Finlay DK (2019) Immunometabolism and natural killer cell responses. Nat Rev Immunol 19:282–290

    PubMed  Google Scholar 

  19. He Y, Tian Z (2017) NK cell education via nonclassical MHC and non-MHC ligands. Cell Mol Immunol 14:321–330

    CAS  PubMed  Google Scholar 

  20. Lysakova-Devine T, O’Farrelly C (2014) Tissue-specific NK cell populations and their origin. J Leukoc Biol 96:981–990

    PubMed  Google Scholar 

  21. Zhang Y, Wallace DL, De Lara CM et al (2007) In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. Immunology 121:258–265

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Walzer T, Bléry M, Chaix J et al (2007) Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46. Proc Natl Acad Sci 104:3384–3389

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang X, Sun R, Hao X, Lian Z-X, Wei H, Tian Z (2019) IL-17 constrains natural killer cell activity by restraining IL-15–driven cell maturation via SOCS3. Proc Natl Acad Sci 116:17409–17418

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Doulatov S, Notta F, Eppert K, Nguyen LT, Ohashi PS, Dick JE (2010) Revised map of the human progenitor hierarchy shows the origin of macrophages and dendritic cells in early lymphoid development. Nat Immunol 11:585

    CAS  PubMed  Google Scholar 

  25. Cichocki F, Grzywacz B, Miller JS (2019) Human NK cell development: one road or many? Front Immunol 10:2078

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Male V, Brady HJ (2014) Transcriptional control of NK cell differentiation and function. Transcr Control Lineage Differ Immune Cells. https://doi.org/10.1007/82_2014_376

    Article  Google Scholar 

  27. Male V, Nisoli I, Kostrzewski T, Allan DS, Carlyle JR, Lord GM, Wack A, Brady HJ (2014) The transcription factor E4bp4/Nfil3 controls commitment to the NK lineage and directly regulates Eomes and Id2 expression. J Exp Med 211:635–642

    CAS  PubMed  PubMed Central  Google Scholar 

  28. de Jonge K, Ebering A, Nassiri S, Maby-El Hajjami H, Ouertatani-Sakouhi H, Baumgaertner P, Speiser DE (2019) Circulating CD56 bright NK cells inversely correlate with survival of melanoma patients. Sci Rep 9:1–10

    Google Scholar 

  29. Crome SQ, Lang PA, Lang KS, Ohashi PS (2013) Natural killer cells regulate diverse T cell responses. Trends Immunol 34:342–349

    CAS  PubMed  Google Scholar 

  30. Ferlazzo G, Thomas D, Lin S-L, Goodman K, Morandi B, Muller WA, Moretta A, Münz C (2004) The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic. J Immunol 172:1455–1462

    CAS  PubMed  Google Scholar 

  31. Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, Carson WE, Caligiuri MA (2001) Human natural killer cells: a unique innate immunoregulatory role for the CD56bright subset. Blood 97:3146–3151

    CAS  PubMed  Google Scholar 

  32. Vosshenrich CA, García-Ojeda ME, Samson-Villéger SI et al (2006) A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127. Nat Immunol 7:1217–1224

    CAS  PubMed  Google Scholar 

  33. Grégoire C, Chasson L, Luci C, Tomasello E, Geissmann F, Vivier E, Walzer T (2007) The trafficking of natural killer cells. Immunol Rev 220:169–182

    PubMed  PubMed Central  Google Scholar 

  34. Wendel M, Galani IE, Suri-Payer E, Cerwenka A (2008) Natural killer cell accumulation in tumors is dependent on IFN-γ and CXCR3 ligands. Can Res 68:8437–8445

    CAS  Google Scholar 

  35. Hydes T, Noll A, Salinas-Riester G et al (2018) IL-12 and IL-15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells. Immun Inflamm Dis 6:34–46

    CAS  PubMed  Google Scholar 

  36. Ishida Y, Migita K, Izumi Y et al (2004) The role of IL-18 in the modulation of matrix metalloproteinases and migration of human natural killer (NK) cells. FEBS Lett 569:156–160

    CAS  PubMed  Google Scholar 

  37. Li C, Ge B, Nicotra M, Stern JN, Kopcow HD, Chen X, Strominger JL (2008) JNK MAP kinase activation is required for MTOC and granule polarization in NKG2D-mediated NK cell cytotoxicity. Proc Natl Acad Sci 105:3017–3022

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Moriggl R, Sexl V, Piekorz R, Topham D, Ihle JN (1999) Stat5 activation is uniquely associated with cytokine signaling in peripheral T cells. Immunity 11:225–230

    CAS  PubMed  Google Scholar 

  39. Samson SI, Richard O, Tavian M et al (2003) GATA-3 promotes maturation, IFN-γ production, and liver-specific homing of NK cells. Immunity 19:701–711

    CAS  PubMed  Google Scholar 

  40. Kallies A, Carotta S, Huntington ND, Bernard NJ, Tarlinton DM, Smyth MJ, Nutt SL (2011) A role for Blimp1 in the transcriptional network controlling natural killer cell maturation. Blood 117:1869–1879

    CAS  PubMed  Google Scholar 

  41. Ohno S-i, Sato T, Kohu K, Takeda K, Okumura K, Satake M, Habu S (2008) Runx proteins are involved in regulation of CD122, Ly49 family and IFN-γ expression during NK cell differentiation. Int Immunol 20:71–79

    CAS  PubMed  Google Scholar 

  42. Campbell JJ, Qin S, Unutmaz D, Soler D, Murphy KE, Hodge MR, Wu L, Butcher EC (2001) Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire. J Immunol 166:6477–6482

    CAS  PubMed  Google Scholar 

  43. Inngjerdingen M, Damaj B, Maghazachi AA (2001) Expression and regulation of chemokine receptors in human natural killer cells. Blood 97:367–375

    CAS  PubMed  Google Scholar 

  44. Edsparr K, Speetjens FM, Mulder-Stapel A, Goldfarb RH, Basse PH, Lennernäs B, Kuppen PJ, Albertsson P (2010) Effects of IL-2 on MMP expression in freshly isolated human NK cells and the IL-2-independent NK cell line YT. J Immunother 33:475 (Hagerstown, Md.: 1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Taub DD, Sayers TJ, Carter C, Ortaldo JR (1995) Alpha and beta chemokines induce NK cell migration and enhance NK-mediated cytolysis. J Immunol 155:3877–3888

    CAS  PubMed  Google Scholar 

  46. Albertsson P, Kim M, Jonges L, Kitson R, Kuppen P, Johansson B, Nannmark U, Goldfarb R (2000) Matrix metalloproteinases of human NK cells. Vivo (Athens, Greece) 14:269–276

    CAS  Google Scholar 

  47. Goda S, Inoue H, Umehara H et al (2006) Matrix metalloproteinase-1 produced by human CXCL12-stimulated natural killer cells. Am J Pathol 169:445–458

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Johnatty RN, Taub DD, Reeder SP, Turcovski-Corrales SM, Cottam DW, Stephenson TJ, Rees RC (1997) Cytokine and chemokine regulation of proMMP-9 and TIMP-1 production by human peripheral blood lymphocytes. J Immunol 158:2327–2333

    CAS  PubMed  Google Scholar 

  49. Quatrini L, Molfetta R, Zitti B et al (2015) Ubiquitin-dependent endocytosis of NKG2D-DAP10 receptor complexes activates signaling and functions in human NK cells. Sci Signal 8:ra108–ra108

    PubMed  Google Scholar 

  50. Sivori S, Vacca P, Del Zotto G, Munari E, Mingari MC, Moretta L (2019) Human NK cells: surface receptors, inhibitory checkpoints, and translational applications. Cell Mol Immunol 16:430–441

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Luu TT, Nguyen N-A, Ganesan S, Meinke S, Kadri N, Alici E, Höglund P (2019) A brief IL-15 pulse results in JAK3-dependent phosphorylation of ITAM-associated signaling molecules and a long-lasting priming imprint in mouse NK cells. SSRN Electron J. https://doi.org/10.2139/ssrn.3351831 (Available at SSRN 3351831)

    Article  Google Scholar 

  52. Raneros AB, Puras AM, Rodriguez RM et al (2017) Increasing TIMP3 expression by hypomethylating agents diminishes soluble MICA, MICB and ULBP2 shedding in acute myeloid leukemia, facilitating NK cell-mediated immune recognition. Oncotarget 8:31959

    PubMed  PubMed Central  Google Scholar 

  53. López-Cobo S, Romera-Cárdenas G, García-Cuesta EM, Reyburn HT, Valés-Gómez M (2015) Transfer of the human NKG 2D ligands UL 16 binding proteins (ULBP) 1–3 is related to lytic granule release and leads to ligand retransfer and killing of ULBP-recipient natural killer cells. Immunology 146:70–80

    PubMed  PubMed Central  Google Scholar 

  54. Yang L, Shen M, Xu LJ, Yang X, Tsai Y, Keng PC, Chen Y, Lee SO (2017) Enhancing NK cell-mediated cytotoxicity to cisplatin-resistant lung cancer cells via MEK/Erk signaling inhibition. Sci Rep 7:1–13

    Google Scholar 

  55. Vivier E, Nunès JA, Vély F (2004) Natural killer cell signaling pathways. Science 306:1517–1519

    CAS  PubMed  Google Scholar 

  56. Smyth MJ, Cretney E, Takeda K, Wiltrout RH, Sedger LM, Kayagaki N, Yagita H, Okumura K (2001) Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) contributes to interferon γ–dependent natural killer cell protection from tumor metastasis. J Exp Med 193:661–670

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Wigginton JM, Gruys E, Geiselhart L et al (2001) IFN-γ and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy. J Clin Investig 108:51–62

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Saric T, Chang S-C, Hattori A, York IA, Markant S, Rock KL, Tsujimoto M, Goldberg AL (2002) An IFN-γ–induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I–presented peptides. Nat Immunol 3:1169–1176

    CAS  PubMed  Google Scholar 

  59. Koya T, Yanagisawa R, Higuchi Y, Sano K, Shimodaira S (2017) Interferon-α-inducible dendritic cells matured with OK-432 exhibit TRAIL and fas ligand pathway-mediated killer activity. Sci Rep 7:1–11

    Google Scholar 

  60. Balkwill FR, Capasso M, Hagemann T (2012) The tumor microenvironment at a glance. J Cell Sci 125(23):5591–5596 (The Company of Biologists Ltd)

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  62. Garris CS, Luke JJ (2020) Dendritic cells, the T-cell-inflamed tumor microenvironment, and immunotherapy treatment response. Clin Cancer Res 26:3901–3907

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Straussman R, Morikawa T, Shee K et al (2012) Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487:500–504

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Khodayari H, Chamani R, Khodayari S, Alizadeh AM (2016) A glance into cancer stem cells. J Kerman Univ Med Sci 23:515–542

    Google Scholar 

  65. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin–cyclophosphamide chemotherapy. Cancer Immunol Immunother 58:49–59

    CAS  PubMed  Google Scholar 

  66. Kono K, Kawaida H, Takahashi A, Sugai H, Mimura K, Miyagawa N, Omata H, Fujii H (2006) CD4 (+) CD25 high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol Immunother 55:1064–1071

    CAS  PubMed  Google Scholar 

  67. Porembka MR, Mitchem JB, Belt BA, Hsieh C-S, Lee H-M, Herndon J, Gillanders WE, Linehan DC, Goedegebuure P (2012) Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol Immunother 61:1373–1385

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Murray S, Lundqvist A (2016) Targeting the tumor microenvironment to improve natural killer cell-based immunotherapies: on being in the right place at the right time, with resilience. Hum Vaccin Immunother 12:607–611

    PubMed  Google Scholar 

  69. Ren J, Zeng W, Tian F, Zhang S, Wu F, Qin X, Zhang Y, Lin Y (2019) Myeloid-derived suppressor cells depletion may cause pregnancy loss via upregulating the cytotoxicity of decidual natural killer cells. Am J Reprod Immunol 81:e13099

    PubMed  Google Scholar 

  70. Hoechst B, Voigtlaender T, Ormandy L et al (2009) Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50:799–807

    CAS  PubMed  Google Scholar 

  71. Li H, Han Y, Guo Q, Zhang M, Cao X (2009) Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-β1. J Immunol 182:240–249

    CAS  PubMed  Google Scholar 

  72. Smyth MJ, Teng MW, Swann J, Kyparissoudis K, Godfrey DI, Hayakawa Y (2006) CD4+ CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J Immunol 176:1582–1587

    CAS  PubMed  Google Scholar 

  73. Littwitz-Salomon E, Malyshkina A, Schimmer S, Dittmer U (2018) The cytotoxic activity of natural killer cells is suppressed by IL-10+ regulatory T cells during acute retroviral infection. Front Immunol 9:1947

    PubMed  PubMed Central  Google Scholar 

  74. Costantini C, Cassatella MA (2011) The defensive alliance between neutrophils and NK cells as a novel arm of innate immunity. J Leukoc Biol 89:221–233

    CAS  PubMed  Google Scholar 

  75. Li T, Yang Y, Hua X, Wang G, Liu W, Jia C, Tai Y, Zhang Q, Chen G (2012) Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett 318:154–161

    CAS  PubMed  Google Scholar 

  76. Li T, Yi S, Liu W, Jia C, Wang G, Hua X, Tai Y, Zhang Q, Chen G (2013) Colorectal carcinoma-derived fibroblasts modulate natural killer cell phenotype and antitumor cytotoxicity. Med Oncol 30:663

    PubMed  Google Scholar 

  77. Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L (2008) Mesenchymal stem cells inhibit natural killer–cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2, 3-dioxygenase and prostaglandin E2. Blood J Am Soc Hematol 111:1327–1333

    CAS  Google Scholar 

  78. Oyer JL, Gitto SB, Altomare DA, Copik AJ (2018) PD-L1 blockade enhances anti-tumor efficacy of NK cells. Oncoimmunology 7:e1509819

    PubMed  PubMed Central  Google Scholar 

  79. Juliá EP, Amante A, Pampena MB, Mordoh J, Levy EM (2018) Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against triple negative breast cancer cells. Front Immunol 9:2140

    PubMed  PubMed Central  Google Scholar 

  80. Sarvaria A, Jawdat D, Madrigal JA, Saudemont A (2017) Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. Front Immunol 8:329

    PubMed  PubMed Central  Google Scholar 

  81. Liang S, Niu L, Xu K, Wang X, Liang Y, Zhang M, Chen J, Lin M (2017) Tumor cryoablation in combination with natural killer cells therapy and herceptin in patients with HER2-overexpressing recurrent breast cancer. Mol Immunol 92:45–53

    CAS  PubMed  Google Scholar 

  82. Lin M, Liang S, Wang X, Liang Y, Zhang M, Chen J, Niu L, Xu K (2017) Percutaneous irreversible electroporation combined with allogeneic natural killer cell immunotherapy for patients with unresectable (stage III/IV) pancreatic cancer: a promising treatment. J Cancer Res Clin Oncol 143:2607–2618

    CAS  PubMed  Google Scholar 

  83. Sakamoto N, Ishikawa T, Kokura S et al (2015) Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J Transl Med 13:1–13

    Google Scholar 

  84. Li R, Wang C, Liu L et al (2012) Autologous cytokine-induced killer cell immunotherapy in lung cancer: a phase II clinical study. Cancer Immunol Immunother 61:2125–2133

    CAS  PubMed  Google Scholar 

  85. Pérez-Martínez A, Fernández L, Valentín J et al (2015) A phase I/II trial of interleukin-15–stimulated natural killer cell infusion after haplo-identical stem cell transplantation for pediatric refractory solid tumors. Cytotherapy 17:1594–1603

    PubMed  Google Scholar 

  86. Ardolino M, Raulet DH (2016) Cytokine therapy restores antitumor responses of NK cells rendered anergic in MHC I-deficient tumors. Oncoimmunology 5:e1002725

    PubMed  Google Scholar 

  87. Fiedler W, Zeller W, Peimann C-J, Weh H-J, Hossfeld D (1991) A phase II combination trial with recombinant human tumor necrosis factor and gamma interferon in patients with colorectal cancer. Klin Wochenschr 69:261–268

    CAS  PubMed  Google Scholar 

  88. Hayakawa M, Hatano T, Ogawa Y, Gakiya M, Ogura H, Osawa A (1994) Treatment of advanced renal cell carcinoma using regional arterial administration of lymphokine-activated killer cells in combination with low doses of rlL-2. Urol Int 53:117–124

    CAS  PubMed  Google Scholar 

  89. Ueda Y, Yamagishi H, Tanioka Y, Fujiwara H, Fuji N, Itoh T, Fujiki H, Yoshimura T, Oka T (1999) Clinical application of adoptive immunotherapy and IL-2 for the treatment of advanced digestive tract cancer. Hepatogastroenterology 46:1274–1279

    CAS  PubMed  Google Scholar 

  90. Law TM, Motzer RJ, Mazumdar M et al (1995) Phase iii randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma. Cancer 76:824–832

    CAS  PubMed  Google Scholar 

  91. Hashimoto W, Tanaka F, Robbins PD, Taniguchi M, Okamura H, Lotze MT, Tahara H (2003) Natural killer, but not natural killer T, cells play a necessary role in the promotion of an innate antitumor response induced by IL-18. Int J Cancer 103:508–513

    CAS  PubMed  Google Scholar 

  92. Del Vecchio M, Bajetta E, Canova S, Lotze MT, Wesa A, Parmiani G, Anichini A (2007) Interleukin-12: biological properties and clinical application. Clin Cancer Res 13:4677–4685

    PubMed  Google Scholar 

  93. Multhoff G, Seier S, Stangl S et al (2020) Targeted natural killer cell-based adoptive immunotherapy for the treatment of patients with NSCLC after radiochemotherapy: a randomized phase II clinical trial. Clin Cancer Res 26:5368–5379

    CAS  PubMed  Google Scholar 

  94. Knorr DA et al (2014) Clinical utility of natural killer cells in cancer therapy and transplantation. Seminars in immunology. Vol 26, No 2. Academic Press

  95. Liang S, Lin M, Niu L, Xu K, Wang X, Liang Y, Zhang M, Du D, Chen J (2018) Cetuximab combined with natural killer cells therapy: an alternative to chemoradiotherapy for patients with advanced non-small cell lung cancer (NSCLC). Am J Cancer Res 8:879

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Ishikawa T, Okayama T, Sakamoto N et al (2018) Phase I clinical trial of adoptive transfer of expanded natural killer cells in combination with I g G 1 antibody in patients with gastric or colorectal cancer. Int J Cancer 142:2599–2609

    CAS  PubMed  Google Scholar 

  97. Arai S, Meagher R, Swearingen M, Myint H, Rich E, Martinson J, Klingemann H (2008) Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy 10:625–632

    CAS  PubMed  Google Scholar 

  98. Suck G, Odendahl M, Nowakowska P, Seidl C, Wels WS, Klingemann HG, Tonn T (2016) NK-92: an ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother 65:485–492

    CAS  PubMed  Google Scholar 

  99. Gong J-H, Maki G, Klingemann HG (1994) Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia 8:652–658

    CAS  PubMed  Google Scholar 

  100. Božič J, Stoka V, Dolenc I (2018) Glucosamine prevents polarization of cytotoxic granules in NK-92 cells by disturbing FOXO1/ERK/paxillin phosphorylation. PLoS ONE 13:e0200757

    PubMed  PubMed Central  Google Scholar 

  101. Montagner IM, Penna A, Fracasso G, Carpanese D, Pietà AD, Barbieri V, Zuccolotto G, Rosato A (2020) Anti-PSMA CAR-engineered NK-92 cells: an off-the-shelf cell therapy for prostate cancer. Cells 9:1382

    CAS  PubMed Central  Google Scholar 

  102. Wu A, Wiesner S, Xiao J, Ericson K, Chen W, Hall WA, Low WC, Ohlfest JR (2007) Expression of MHC I and NK ligands on human CD133+ glioma cells: possible targets of immunotherapy. J Neurooncol 83:121–131

    CAS  PubMed  Google Scholar 

  103. Bolourian A, Mojtahedi Z (2017) Possible damage to immune-privileged sites in natural killer cell therapy in cancer patients: side effects of natural killer cell therapy. Immunotherapy 9:281–288

    CAS  PubMed  Google Scholar 

  104. Ishikawa E, Tsuboi K, Saijo K, Harada H, Takano S, Nose T, Ohno T (2004) Autologous natural killer cell therapy for human recurrent malignant glioma. Anticancer Res 24:1861–1871

    PubMed  Google Scholar 

  105. Mantia CM, Buchbinder EI (2019) Immunotherapy toxicity. hematology/oncology. Clinics 33:275–290

    Google Scholar 

  106. Haanen J, Carbonnel F, Robert C, Kerr K, Peters S, Larkin J, Jordan K (2017) Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 28:iv119–iv142

    CAS  PubMed  Google Scholar 

  107. Liu D, Tian S, Zhang K, Xiong W, Lubaki NM, Chen Z, Han W (2017) Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV. Prot Cell 8:861–877

    CAS  Google Scholar 

  108. Barkholt L, Alici E, Conrad R et al (2009) Safety analysis of ex vivo-expanded NK and NK-like T cells administered to cancer patients: a phase I clinical study. Immunotherapy 1:753–764

    CAS  PubMed  Google Scholar 

  109. Iliopoulou EG, Kountourakis P, Karamouzis MV, Doufexis D, Ardavanis A, Baxevanis CN, Rigatos G, Papamichail M, Perez SA (2010) A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Cancer Immunol Immunother 59:1781–1789

    PubMed  Google Scholar 

  110. Yang YJ, Park JC, Kim HK, Kang JH, Park SY (2013) A trial of autologous ex vivo-expanded NK cell-enriched lymphocytes with docetaxel in patients with advanced non-small cell lung cancer as second-or third-line treatment: phase IIa study. Anticancer Res 33:2115–2122

    CAS  PubMed  Google Scholar 

  111. Motohashi S, Ishikawa A, Ishikawa E et al (2006) A phase I study of in vitro expanded natural killer T cells in patients with advanced and recurrent non–small cell lung cancer. Clin Cancer Res 12:6079–6086

    CAS  PubMed  Google Scholar 

  112. Parkhurst MR, Riley JP, Dudley ME, Rosenberg SA (2011) Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin Cancer Res 17:6287–6297

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Lin M, Xu K, Liang S, Wang X, Liang Y, Zhang M, Chen J, Niu L (2017) Prospective study of percutaneous cryoablation combined with allogenic NK cell immunotherapy for advanced renal cell cancer. Immunol Lett 184:98–104

    CAS  PubMed  Google Scholar 

  114. Dillman RO, Duma CM, Ellis RA, Cornforth AN, Schiltz PM, Sharp SL, DePriest MC (2009) Intralesional lymphokine-activated killer cells as adjuvant therapy for primary glioblastoma. J Immunother 32:914–919

    PubMed  Google Scholar 

  115. Tonn T, Schwabe D, Klingemann HG et al (2013) Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy 15:1563–1570

    CAS  PubMed  Google Scholar 

  116. Geller MA, Cooley S, Judson PL et al (2011) A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy 13:98–107

    CAS  PubMed  Google Scholar 

  117. Mardanpour P, Nayernia K, Khodayari S, Khodayari H, Molcanyi M, Hescheler J (2019) Application of stem cell technologies to regenerate injured myocardium and improve cardiac function. Cell Physiol Biochem 53:101–120

    CAS  PubMed  Google Scholar 

  118. Khodayari S, Khodayari H, Amiri AZ, Eslami M, Farhud D, Hescheler J, Nayernia K (2019) Inflammatory microenvironment of acute myocardial infarction prevents regeneration of heart with stem cells therapy. Cell Physiol Biochem 53:887–909

    CAS  PubMed  Google Scholar 

  119. Nayernia K, Nolte J, Michelmann HW et al (2006) In vitro-differentiated embryonic stem cells give rise to male gametes that can generate offspring mice. Dev Cell 11:125–132

    CAS  PubMed  Google Scholar 

  120. Guan K, Nayernia K, Maier LS et al (2006) Pluripotency of spermatogonial stem cells from adult mouse testis. Nature 440:1199–1203

    CAS  PubMed  Google Scholar 

  121. Mitalipov S, Wolf D (2009) Totipotency, pluripotency and nuclear reprogramming. Engineering of stem cells. Springer, Berlin, pp 185–199

    Google Scholar 

  122. De Paepe C, Krivega M, Cauffman G, Geens M, Van de Velde H (2014) Totipotency and lineage segregation in the human embryo. Mol Hum Reprod 20:599–618

    PubMed  Google Scholar 

  123. Ishiuchi T, Torres-Padilla M-E (2013) Towards an understanding of the regulatory mechanisms of totipotency. Curr Opin Genet Dev 23:512–518

    CAS  PubMed  Google Scholar 

  124. Zhou L-q, Dean J (2015) Reprogramming the genome to totipotency in mouse embryos. Trends Cell Biol 25:82–91

    CAS  PubMed  Google Scholar 

  125. Falco G, Lee S-L, Stanghellini I, Bassey UC, Hamatani T, Ko MS (2007) Zscan4: a novel gene expressed exclusively in late 2-cell embryos and embryonic stem cells. Dev Biol 307:539–550

    CAS  PubMed  PubMed Central  Google Scholar 

  126. De Iaco A, Planet E, Coluccio A, Verp S, Duc J, Trono D (2017) DUX-family transcription factors regulate zygotic genome activation in placental mammals. Nat Genet 49:941–945

    PubMed  PubMed Central  Google Scholar 

  127. Hendrickson PG, Doráis JA, Grow EJ et al (2017) Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nat Genet 49:925–934

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Fadloun A, Le Gras S, Jost B, Ziegler-Birling C, Takahashi H, Gorab E, Carninci P, Torres-Padilla M-E (2013) Chromatin signatures and retrotransposon profiling in mouse embryos reveal regulation of LINE-1 by RNA. Nat Struct Mol Biol 20:332

    CAS  PubMed  Google Scholar 

  129. Hu Z, Tan DEK, Chia G et al (2020) Maternal factor NELFA drives a 2C-like state in mouse embryonic stem cells. Nat Cell Biol 22:175–186

    CAS  PubMed  Google Scholar 

  130. King NM, Perrin J (2014) Ethical issues in stem cell research and therapy. St Cell Res Ther 5:1–6

    CAS  Google Scholar 

  131. Yilmaz A, Benvenisty N (2019) Defining human pluripotency. Cell St Cell 25:9–22

    CAS  Google Scholar 

  132. Boroviak T, Loos R, Bertone P, Smith A, Nichols J (2014) The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification. Nat Cell Biol 16:513–525

    Google Scholar 

  133. Sugimura R, Jha DK, Han A et al (2017) Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 545:432–438

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Woll PS, Grzywacz B, Tian X, Marcus RK, Knorr DA, Verneris MR, Kaufman DS (2009) Human embryonic stem cells differentiate into a homogeneous population of natural killer cells with potent in vivo antitumor activity. Blood 113:6094–6101

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Schmidt R, Plath K (2012) The roles of the reprogramming factors Oct4, Sox2 and Klf4 in resetting the somatic cell epigenome during induced pluripotent stem cell generation. Genome Biol 13:1–11

    Google Scholar 

  136. Fiedorowicz K, Rozwadowska N, Zimna A et al (2020) Tissue-specific promoter-based reporter system for monitoring cell differentiation from iPSCs to cardiomyocytes. Sci Rep 10:1–13

    Google Scholar 

  137. Wang Y, Mah N, Prigione A, Wolfrum K, Andrade-Navarro MA, Adjaye J (2010) A transcriptional roadmap to the induction of pluripotency in somatic cells. St Cell Rev Rep 6:282–296

    CAS  Google Scholar 

  138. Castro-Viñuelas R, Sanjurjo-Rodríguez C, Piñeiro-Ramil M et al (2020) Generation and characterization of human induced pluripotent stem cells (iPSCs) from hand osteoarthritis patient-derived fibroblasts. Sci Rep 10:1–13

    Google Scholar 

  139. Kim Y, Rim YA, Yi H, Park N, Park S-H, Ju JH (2016) The generation of human induced pluripotent stem cells from blood cells: an efficient protocol using serial plating of reprogrammed cells by centrifugation. St Cells Int 2016:1–9

    Google Scholar 

  140. Seki T, Yuasa S, Oda M et al (2010) Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell St Cell 7:11–14

    CAS  Google Scholar 

  141. Zhou T, Benda C, Dunzinger S et al (2012) Generation of human induced pluripotent stem cells from urine samples. Nat Protoc 7:2080

    CAS  PubMed  Google Scholar 

  142. Zapata-Linares N, Rodriguez S, Mazo M, Abizanda G, Andreu EJ, Barajas M, Prosper F, Rodriguez-Madoz JR (2016) Generation and characterization of human iPSC line generated from mesenchymal stem cells derived from adipose tissue. St Cell Res 16:20–23

    CAS  Google Scholar 

  143. Wu KH, Wang SY, Xiao QR, Yang Y, Huang NP, Mo XM, Sun J (2019) Small-molecule–based generation of functional cardiomyocytes from human umbilical cord–derived induced pluripotent stem cells. J Cell Biochem 120:1318–1327

    CAS  Google Scholar 

  144. Yulin X, Lizhen L, Lifei Z, Shan F, Ru L, Kaimin H, Huang H (2012) Efficient generation of induced pluripotent stem cells from human bone marrow mesenchymal stem cells. Folia Biol 58:221

    CAS  Google Scholar 

  145. Teng YD (2019) Functional multipotency of stem cells: biological traits gleaned from neural progeny studies. Seminars in cell & developmental biology. Elsevier, pp 74–83

    Google Scholar 

  146. Wu Y, Zeng J, Roscoe BP et al (2019) Highly efficient therapeutic gene editing of human hematopoietic stem cells. Nat Med 25:776–783

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Zou Y, Zhao Y, Xiao Z, Chen B, Ma D, Shen H, Gu R, Dai J (2020) Comparison of regenerative effects of transplanting three-dimensional longitudinal scaffold loaded-human mesenchymal stem cells and human neural stem cells on spinal cord completely transected rats. ACS Biomater Sci Eng 6:1671–1680

    CAS  PubMed  Google Scholar 

  148. Khodayari S, Khodayari H, Alizadeh AM (2016) A glance into the future cardiac stem cells. Tehran Univ Med J TUMS Publ 74:223–235

    Google Scholar 

  149. Goodarzi A, Khanmohammadi M, Ai A et al (2020) Simultaneous impact of atorvastatin and mesenchymal stem cells for glioblastoma multiform suppression in rat glioblastoma multiform model. Mol Biol Rep 47:7783–7795

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Yvernogeau L, Gautier R, Petit L et al (2019) In vivo generation of haematopoietic stem/progenitor cells from bone marrow-derived haemogenic endothelium. Nat Cell Biol 21:1334–1345

    CAS  PubMed  Google Scholar 

  151. Kao I-T, Yao C-L, Kong Z-L, Wu M-L, Chuang T-L, Hwang S-M (2007) Generation of natural killer cells from serum-free, expanded human umbilical cord blood CD34+ cells. St Cells Dev 16:1043–1052

    CAS  Google Scholar 

  152. Chen Y-R, Yan X, Yuan F-Z et al (2020) The use of peripheral blood-derived stem cells for cartilage repair and regeneration in vivo: a review. Front Pharmacol. https://doi.org/10.3389/fphar.2020.00404

    Article  PubMed  PubMed Central  Google Scholar 

  153. Blanchet M-R, Bennett JL, Gold MJ, Levantini E, Tenen DG, Girard M, Cormier Y, McNagny KM (2011) CD34 is required for dendritic cell trafficking and pathology in murine hypersensitivity pneumonitis. Am J Respir Crit Care Med 184:687–698

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Knorr DA, Ni Z, Hermanson D, Hexum MK, Bendzick L, Cooper LJ, Lee DA, Kaufman DS (2013) Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. St Cells Transl Med 2:274–283

    CAS  Google Scholar 

  155. Tabatabaei-Zavareh N, Vlasova A, Greenwood CP, Takei F (2007) Characterization of developmental pathway of natural killer cells from embryonic stem cells in vitro. PLoS ONE 2:e232

    PubMed  PubMed Central  Google Scholar 

  156. Miller JS, Alley KA, McGlave P (1994) Differentiation of natural killer (NK) cells from human primitive marrow progenitors in a stroma-based long-term culture system: identification of a CD34+ 7+ NK progenitor. Blood 83(9):2594–2601

    CAS  PubMed  Google Scholar 

  157. Woll PS, Martin CH, Miller JS, Kaufman DS (2005) Human embryonic stem cell-derived NK cells acquire functional receptors and cytolytic activity. J Immunol 175:5095–5103

    CAS  PubMed  Google Scholar 

  158. Ni Z, Knorr DA, Clouser CL, Hexum MK, Southern P, Mansky LM, Park I-H, Kaufman DS (2011) Human pluripotent stem cells produce natural killer cells that mediate anti-HIV-1 activity by utilizing diverse cellular mechanisms. J Virol 85:43–50

    CAS  PubMed  Google Scholar 

  159. Bonanno G, Mariotti A, Procoli A, Corallo M, Scambia G, Pierelli L, Rutella S (2009) Interleukin-21 induces the differentiation of human umbilical cord blood CD34-lineage-cells into pseudomature lytic NK cells. BMC Immunol 10:1–15

    Google Scholar 

  160. McCullar V, Oostendorp R, Panoskaltsis-Mortari A, Yun G, Lutz CT, Wagner JE, Miller JS (2008) Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15. Exp Hematol 36:598–608

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Frias AM, Porada CD, Crapnell KB, Cabral JM, Zanjani ED, Almeida-Porada G (2008) Generation of functional natural killer and dendritic cells in a human stromal-based serum-free culture system designed for cord blood expansion. Exp Hematol 36:61–68

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Luevano M, Madrigal A, Saudemont A (2012) Generation of natural killer cells from hematopoietic stem cells in vitro for immunotherapy. Cell Mol Immunol 9:310–320

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Grzywacz B, Kataria N, Sikora M, Oostendorp RA, Dzierzak EA, Blazar BR, Miller JS, Verneris MR (2006) Coordinated acquisition of inhibitory and activating receptors and functional properties by developing human natural killer cells. Blood 108:3824–3833

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Perez SA, Mahaira LG, Sotiropoulou PA et al (2006) Effect of IL-21 on NK cells derived from different umbilical cord blood populations. Int Immunol 18:49–58

    CAS  PubMed  Google Scholar 

  165. Ning H, Lei H-E, Xu Y-D, Guan R-L, Venstrom JM, Lin G, Lue TF, Xin Z, Lin C-S (2014) Conversion of adipose-derived stem cells into natural killer-like cells with anti-tumor activities in nude mice. PLoS ONE 9:e106246

    PubMed  PubMed Central  Google Scholar 

  166. Spanholtz J, Preijers F, Tordoir M, Trilsbeek C, Paardekooper J, De Witte T, Schaap N, Dolstra H (2011) Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. PLoS ONE 6:e20740

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Davis ZB, Felices M, Verneris MR, Miller JS (2015) Natural killer cell adoptive transfer therapy: exploiting the first line of defense against cancer. Cancer J Sudbury Mass 21:486

    CAS  Google Scholar 

  168. Miller JS, Soignier Y, Panoskaltsis-Mortari A et al (2005) Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105:3051–3057

    CAS  PubMed  Google Scholar 

  169. Lehmann D, Spanholtz J, Osl M, Tordoir M, Lipnik K, Bilban M, Schlechta B, Dolstra H, Hofer E (2012) Ex vivo generated natural killer cells acquire typical natural killer receptors and display a cytotoxic gene expression profile similar to peripheral blood natural killer cells. St Cells Dev 21:2926–2938

    CAS  Google Scholar 

  170. Sadelain M, Rivière I, Riddell S (2017) Therapeutic T cell engineering. Nature 545:423–431

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Wang W, Jiang J, Wu C (2020) CAR-NK for tumor immunotherapy: clinical transformation and future prospects. Cancer Lett 472:175–180

    CAS  PubMed  Google Scholar 

  172. Siegler EL, Zhu Y, Wang P, Yang L (2018) Off-the-shelf CAR-NK cells for cancer immunotherapy. Cell St Cell 23:160–161

    CAS  Google Scholar 

  173. Li Y, Hermanson DL, Moriarity BS, Kaufman DS (2018) Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell St Cell 23:181–192

    CAS  Google Scholar 

  174. Veluchamy JP, Kok N, van der Vliet HJ, Verheul HM, de Gruijl TD, Spanholtz J (2017) The rise of allogeneic natural killer cells as a platform for cancer immunotherapy: recent innovations and future developments. Front Immunol 8:631

    PubMed  PubMed Central  Google Scholar 

  175. Torikai H, Mi T, Gragert L et al (2016) Genetic editing of HLA expression in hematopoietic stem cells to broaden their human application. Sci Rep 6:1–11

    Google Scholar 

  176. Carlsten M, Childs RW (2015) Genetic manipulation of NK cells for cancer immunotherapy: techniques and clinical implications. Front Immunol 6:266

    PubMed  PubMed Central  Google Scholar 

  177. Kooreman NG, Kim Y, de Almeida PE et al (2018) Autologous iPSC-based vaccines elicit anti-tumor responses in vivo. Cell St Cell 22:501–513

    CAS  Google Scholar 

  178. Mrózek 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):2632–2640

    PubMed  Google Scholar 

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Acknowledgements

The figures were created by using of “BioRender.com” and CorelDRAW Graphics Suite X8 (version 2018).

Funding

This research was funded by International Center for Personalized Medicine (ICPM), Düsseldorf, Germany (grant number: ICPM-2019–001).

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Author notes

  1. Hamid Khodayari and Saeed Khodayari have contributed equally.

Authors and Affiliations

  1. International Center for Personalized Medicine (ICPM), 40235, Düsseldorf, Germany

    Hamid Khodayari, Saeed Khodayari, Miko Vesovic & Karim Nayernia

  2. Breast Disease Research Center (BDRC), Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

    Hamid Khodayari, Saeed Khodayari, Farimah Hadjilooei & Habibollah Mahmoodzadeh

  3. Cancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran

    Elmira Ebrahimi

  4. Princess Margaret Cancer Center, University of Toronto, Toronto, Canada

    Farimah Hadjilooei

  5. Institute of Neurophysiology, University of Cologne, Cologne, Germany

    Tomo Saric & Jürgen Hescheler

  6. Cologne Center for Immunoncology (IOZK), Cologne, Germany

    Wilfried Stücker & Stefaan Van Gool

  7. International Stem Cell Academy, 40235, Düsseldorf, Germany

    Jürgen Hescheler & Karim Nayernia

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Contributions

HK, SK, HM, KN, and JH designed the study; HK, SK, EE, and FH wrote the manuscript; SK, HK, and EE were involved in graphical art works and tables; MV, EE, HM, FH, KN, JH, TS, WS, and SVG critically revised the work; KN and HM were involved in supervision.

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Correspondence to Habibollah Mahmoodzadeh or Karim Nayernia.

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Khodayari, H., Khodayari, S., Ebrahimi, E. et al. Stem cells-derived natural killer cells for cancer immunotherapy: current protocols, feasibility, and benefits of ex vivo generated natural killer cells in treatment of advanced solid tumors. Cancer Immunol Immunother 70, 3369–3395 (2021). https://doi.org/10.1007/s00262-021-02975-8

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