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Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias

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Abstract

It is well established that natural killer (NK) cells play an important role in the immunity against cancer, while the involvement of other recently identified, NK-related innate lymphoid cells is still poorly defined. In the haploidentical hematopoietic stem cell transplantation for the therapy of high-risk leukemias, NK cells have been shown to exert a key role in killing leukemic blasts residual after conditioning. While the clinical results in the cure of leukemias are excellent, the exploitation of NK cells in the therapy of solid tumors is still limited and unsatisfactory. In solid tumors, NK cell function may be inhibited via different mechanisms, occurring primarily at the tumor site. The cellular interactions in the tumor microenvironment involve tumor cells, stromal cells and resident or recruited leukocytes and may favor tumor evasion from the host’s defenses. In this context, a number of cytokines, growth factors and enzymes synthesized by tumor cells, stromal cells, suppressive/regulatory myeloid and lymphoid cells may substantially impair the function of different tumor-reactive effector cells, including NK cells. The identification and characterization of such mechanisms may offer clues for the development of new immunotherapeutic strategies to restore effective anti-tumor responses. In order to harness NK cell-based immunotherapies, several approaches have been proposed, including reinforcement of NK cell cytotoxicity by means of specific cytokines, antibodies or drugs. These new tools may improve NK cell function and/or increase tumor susceptibility to NK-mediated killing. Hence, the integration of NK-based immunotherapies with conventional anti-tumor therapies may increase chances of successful cancer treatment.

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Abbreviations

ACT:

Adoptive cell transfer

ADCC:

Antibody-dependent cell-mediated cytotoxicity

ALL:

Acute lymphoblastic leukemia

AML:

Acute myeloid leukemia

BAT3/BAG6:

HLA-B-associated transcript 3/BCL2-associated athanogene 6

BM:

Bone marrow

CAR:

Chimeric antigen receptors

DNAM-1:

DNAX accessory molecule-1

EBV:

Epstein–barr virus

ELS:

Ectopic lymphoid structures

GvHD:

Graft-versus-host disease

GvL:

Graft-versus-leukemia

HCC:

Hepatocellular carcinoma

HSC:

Hematopoietic stem cell

HSCT:

Hematopoietic stem cell transplant

HSP-90:

Heat-shock protein 90

IDO:

Indoleamine 2,3-dioxygenase

IFN-γ:

Interferon-γ

IL:

Interleukin

ILC:

Innate lymphoid cells

KIRs:

Killer cell Ig-like receptors

LAK:

Lymphokine-activated killer

LSC:

Leukemic stem cells

LTi:

Lymphoid tissue inducer

mAbs:

Monoclonal antibodies

MDSC:

Myeloid-derived suppressor cells

MICA:

MHC class I chain-related gene A

MIF:

Migration inhibitory factor

MSC:

Mesenchymal stem cells

MUC16:

Mucin 16

NIMA:

Non-inherited maternal antigen

NK:

Natural killer

NKG2D:

Natural killer group 2, member D

PB:

Peripheral blood

PCNA:

Proliferating cell nuclear antigen

PE-NK cells:

Pleural effusions

PGE2:

Prostaglandin E2

PS:

Phosphatidylserine

SLOs:

Secondary lymphoid organs

TAF:

Tumor-associated fibroblasts

TAM:

Tumor-associated macrophages

TGF-β:

Transforming growth factor-β

TNF-α:

Tumor necrosis factor-α

TRAIL:

TNF-related apoptosis-inducing ligand

Tregs:

Regulatory T cells

VPA:

Sodium valproate

References

  1. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM, Ugolini S (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331(6013):44–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Shi FD, Ljunggren HG, La Cava A, Van Kaer L (2011) Organ-specific features of natural killer cells. Nat Rev Immunol 11(10):658–671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cerwenka A, Lanier LL (2001) Natural killer cells, viruses and cancer. Nat Rev Immunol 1(1):41–49

    Article  CAS  PubMed  Google Scholar 

  4. Fauriat C, Long EO, Ljunggren HG, Bryceson YT (2010) Regulation of human NK-cell cytokine and chemokine production by target cell recognition. Blood 115(11):2167–2176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bryceson YT, March ME, Ljunggren HG, Long EO (2006) Activation, coactivation, and costimulation of resting human natural killer cells. Immunol Rev 214:73–91

    Article  CAS  PubMed  Google Scholar 

  6. Moretta A, Bottino C, Vitale M, Pende D, Biassoni R, Mingari MC, Moretta L (1996) Receptors for HLA class-I molecules in human natural killer cells. Annu Rev Immunol 14:619–648

    Article  CAS  PubMed  Google Scholar 

  7. Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, Biassoni R, Moretta L (2001) Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 19:197–223

    Article  CAS  PubMed  Google Scholar 

  8. Moretta L, Bottino C, Pende D, Mingari MC, Biassoni R, Moretta A (2002) Human natural killer cells: their origin, receptors and function. Eur J Immunol 32(5):1205–1211

    Article  CAS  PubMed  Google Scholar 

  9. Moretta L, Bottino C, Pende D, Vitale M, Mingari MC, Moretta A (2004) Different checkpoints in human NK-cell activation. Trends Immunol 25(12):670–676

    Article  CAS  PubMed  Google Scholar 

  10. Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22(11):633–640

    Article  CAS  PubMed  Google Scholar 

  11. Caligiuri MA (2008) Human natural killer cells. Blood 112(3):461–469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Montaldo E, Del Zotto G, Della Chiesa M, Mingari MC, Moretta A, De Maria A, Moretta L (2013) Human NK cell receptors/markers: a tool to analyze NK cell development, subsets and function. Cytometry A 83(8):702–713

    Article  PubMed  Google Scholar 

  13. Carrega P, Bonaccorsi I, Di Carlo E, Morandi B, Paul P, Rizzello V, Cipollone G, Navarra G, Mingari MC, Moretta L, Ferlazzo G (2014) CD56(bright)perforin(low) noncytotoxic human NK cells are abundant in both healthy and neoplastic solid tissues and recirculate to secondary lymphoid organs via afferent lymph. J Immunol 192(8):3805–3815

    Article  CAS  PubMed  Google Scholar 

  14. Carrega P, Ferlazzo G (2012) Natural killer cell distribution and trafficking in human tissues. Front Immunol 3:347

    Article  PubMed  PubMed Central  Google Scholar 

  15. Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Koyasu S, Locksley RM, McKenzie AN, Mebius RE, Powrie F, Vivier E (2013) Innate lymphoid cells—a proposal for uniform nomenclature. Nat Rev Immunol 13(2):145–149

    Article  CAS  PubMed  Google Scholar 

  16. Eberl G, Di Santo JP, Vivier E (2015) The brave new world of innate lymphoid cells. Nat Immunol 16(1):1–5

    Article  CAS  PubMed  Google Scholar 

  17. Bernink JH, Peters CP, Munneke M, te Velde AA, Meijer SL, Weijer K, Hreggvidsdottir HS, Heinsbroek SE, Legrand N, Buskens CJ, Bemelman WA, Mjosberg JM, Spits H (2013) Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol 14(3):221–229

    Article  CAS  PubMed  Google Scholar 

  18. Fuchs A, Vermi W, Lee JS, Lonardi S, Gilfillan S, Newberry RD, Cella M, Colonna M (2013) Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells. Immunity 38(4):769–781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Barlow JL, McKenzie AN (2014) Type-2 innate lymphoid cells in human allergic disease. Curr Opin Allergy Clin Immunol 14(5):397–403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Goto Y, Obata T, Kunisawa J, Sato S, Ivanov II, Lamichhane A, Takeyama N, Kamioka M, Sakamoto M, Matsuki T, Setoyama H, Imaoka A, Uematsu S, Akira S, Domino SE, Kulig P, Becher B, Renauld JC, Sasakawa C, Umesaki Y, Benno Y, Kiyono H (2014) Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 345(6202):1254009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Vacca P, Montaldo E, Croxatto D, Loiacono F, Canegallo F, Venturini PL, Moretta L, Mingari MC (2015) Identification of diverse innate lymphoid cells in human decidua. Mucosal Immunol 8(2):254–264

    Article  CAS  PubMed  Google Scholar 

  22. Dyring-Andersen B, Geisler C, Agerbeck C, Lauritsen JP, Gudjonsdottir SD, Skov L, Bonefeld CM (2014) Increased number and frequency of group 3 innate lymphoid cells in nonlesional psoriatic skin. Br J Dermatol 170(3):609–616

    Article  CAS  PubMed  Google Scholar 

  23. Kirchberger S, Royston DJ, Boulard O, Thornton E, Franchini F, Szabady RL, Harrison O, Powrie F (2013) Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J Exp Med 210(5):917–931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dieu-Nosjean MC, Goc J, Giraldo NA, Sautes-Fridman C, Fridman WH (2014) Tertiary lymphoid structures in cancer and beyond. Trends Immunol 35(11):571–580

    Article  CAS  PubMed  Google Scholar 

  25. Pitzalis C, Jones GW, Bombardieri M, Jones SA (2014) Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat Rev Immunol 14(7):447–462

    Article  CAS  PubMed  Google Scholar 

  26. Burke S, Lakshmikanth T, Colucci F, Carbone E (2010) New views on natural killer cell-based immunotherapy for melanoma treatment. Trends Immunol 31(9):339–345

    Article  CAS  PubMed  Google Scholar 

  27. Carrega P, Morandi B, Costa R, Frumento G, Forte G, Altavilla G, Ratto GB, Mingari MC, Moretta L, Ferlazzo G (2008) Natural killer cells infiltrating human nonsmall-cell lung cancer are enriched in CD56 bright CD16(−) cells and display an impaired capability to kill tumor cells. Cancer 112(4):863–875

    Article  PubMed  Google Scholar 

  28. Mamessier E, Sylvain A, Thibult ML, Houvenaeghel G, Jacquemier J, Castellano R, Goncalves A, Andre P, Romagne F, Thibault G, Viens P, Birnbaum D, Bertucci F, Moretta A, Olive D (2011) Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J Clin Invest 121(9):3609–3622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Platonova S, Cherfils-Vicini J, Damotte D, Crozet L, Vieillard V, Validire P, Andre P, Dieu-Nosjean MC, Alifano M, Regnard JF, Fridman WH, Sautes-Fridman C, Cremer I (2011) Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res 71(16):5412–5422

    Article  CAS  PubMed  Google Scholar 

  30. Konjevic G, Mirjacic Martinovic K, Vuletic A, Jovic V, Jurisic V, Babovic N, Spuzic I (2007) Low expression of CD161 and NKG2D activating NK receptor is associated with impaired NK cell cytotoxicity in metastatic melanoma patients. Clin Exp Metastasis 24(1):1–11

    Article  CAS  PubMed  Google Scholar 

  31. Lee JC, Lee KM, Kim DW, Heo DS (2004) Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol 172(12):7335–7340

    Article  CAS  PubMed  Google Scholar 

  32. Costello RT, Sivori S, Marcenaro E, Lafage-Pochitaloff M, Mozziconacci MJ, Reviron D, Gastaut JA, Pende D, Olive D, Moretta A (2002) Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia. Blood 99(10):3661–3667

    Article  CAS  PubMed  Google Scholar 

  33. Halama N, Braun M, Kahlert C, Spille A, Quack C, Rahbari N, Koch M, Weitz J, Kloor M, Zoernig I, Schirmacher P, Brand K, Grabe N, Falk CS (2011) Natural killer cells are scarce in colorectal carcinoma tissue despite high levels of chemokines and cytokines. Clin Cancer Res 17(4):678–689

    Article  CAS  PubMed  Google Scholar 

  34. Balsamo M, Scordamaglia F, Pietra G, Manzini C, Cantoni C, Boitano M, Queirolo P, Vermi W, Facchetti F, Moretta A, Moretta L, Mingari MC, Vitale M (2009) Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc Natl Acad Sci USA 106(49):20847–20852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, Biassoni R, Bottino C, Moretta L, Moretta A (2003) Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci USA 100(7):4120–4125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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

    Article  CAS  PubMed  Google Scholar 

  37. Marcenaro E, Della Chiesa M, Bellora F, Parolini S, Millo R, Moretta L, Moretta A (2005) IL-12 or IL-4 prime human NK cells to mediate functionally divergent interactions with dendritic cells or tumors. J Immunol 174(7):3992–3998

    Article  CAS  PubMed  Google Scholar 

  38. Ghiringhelli F, Menard C, Martin F, Zitvogel L (2006) The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression. Immunol Rev 214:229–238

    Article  CAS  PubMed  Google Scholar 

  39. Ghiringhelli F, Menard C, Terme M, Flament C, Taieb J, Chaput N, Puig PE, Novault S, Escudier B, Vivier E, Lecesne A, Robert C, Blay JY, Bernard J, Caillat-Zucman S, Freitas A, Tursz T, Wagner-Ballon O, Capron C, Vainchencker W, Martin F, Zitvogel L (2005) CD4+ CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med 202(8):1075–1085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sitrin J, Ring A, Garcia KC, Benoist C, Mathis D (2013) Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2. J Exp Med 210(6):1153–1165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H, Lehner F, Manns MP, Greten TF, Korangy F (2009) Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50(3):799–807

    Article  CAS  PubMed  Google Scholar 

  42. Sprinzl MF, Reisinger F, Puschnik A, Ringelhan M, Ackermann K, Hartmann D, Schiemann M, Weinmann A, Galle PR, Schuchmann M, Friess H, Otto G, Heikenwalder M, Protzer U (2013) Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells. Hepatology 57(6):2358–2368

    Article  CAS  PubMed  Google Scholar 

  43. 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(2):154–161

    Article  CAS  PubMed  Google Scholar 

  44. 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(3):663

    Article  PubMed  CAS  Google Scholar 

  45. El-Gazzar A, Groh V, Spies T (2013) Immunobiology and conflicting roles of the human NKG2D lymphocyte receptor and its ligands in cancer. J Immunol 191(4):1509–1515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Krockenberger M, Dombrowski Y, Weidler C, Ossadnik M, Honig A, Hausler S, Voigt H, Becker JC, Leng L, Steinle A, Weller M, Bucala R, Dietl J, Wischhusen J (2008) Macrophage migration inhibitory factor contributes to the immune escape of ovarian cancer by down-regulating NKG2D. J Immunol 180(11):7338–7348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gubbels JA, Felder M, Horibata S, Belisle JA, Kapur A, Holden H, Petrie S, Migneault M, Rancourt C, Connor JP, Patankar MS (2010) MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells. Mol Cancer 9:11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Castriconi R, Dondero A, Bellora F, Moretta L, Castellano A, Locatelli F, Corrias MV, Moretta A, Bottino C (2013) Neuroblastoma-derived TGF-beta1 modulates the chemokine receptor repertoire of human resting NK cells. J Immunol 190(10):5321–5328

    Article  CAS  PubMed  Google Scholar 

  49. Balsamo M, Manzini C, Pietra G, Raggi F, Blengio F, Mingari MC, Varesio L, Moretta L, Bosco MC, Vitale M (2013) Hypoxia downregulates the expression of activating receptors involved in NK-cell-mediated target cell killing without affecting ADCC. Eur J Immunol 43(10):2756–2764

    Article  CAS  PubMed  Google Scholar 

  50. Balsamo M, Vermi W, Parodi M, Pietra G, Manzini C, Queirolo P, Lonardi S, Augugliaro R, Moretta A, Facchetti F, Moretta L, Mingari MC, Vitale M (2012) Melanoma cells become resistant to NK-cell-mediated killing when exposed to NK-cell numbers compatible with NK-cell infiltration in the tumor. Eur J Immunol 42(7):1833–1842

    Article  CAS  PubMed  Google Scholar 

  51. Pogge von Strandmann E, Simhadri VR, von Tresckow B, Sasse S, Reiners KS, Hansen HP, Rothe A, Boll B, Simhadri VL, Borchmann P, McKinnon PJ, Hallek M, Engert A (2007) Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. Immunity 27(6):965–974

    Article  CAS  PubMed  Google Scholar 

  52. Reiners KS, Topolar D, Henke A, Simhadri VR, Kessler J, Sauer M, Bessler M, Hansen HP, Tawadros S, Herling M, Kronke M, Hallek M, Pogge von Strandmann E (2013) Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity. Blood 121(18):3658–3665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Rosental B, Brusilovsky M, Hadad U, Oz D, Appel MY, Afergan F, Yossef R, Rosenberg LA, Aharoni A, Cerwenka A, Campbell KS, Braiman A, Porgador A (2011) Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44. J Immunol 187(11):5693–5702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Horton NC, Mathew SO, Mathew PA (2013) Novel interaction between proliferating cell nuclear antigen and HLA I on the surface of tumor cells inhibits NK cell function through NKp44. PLoS ONE 8(3):e59552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cantoni C, Bottino C, Augugliaro R, Morelli L, Marcenaro E, Castriconi R, Vitale M, Pende D, Sivori S, Millo R, Biassoni R, Moretta L, Moretta A (1999) Molecular and functional characterization of IRp60, a member of the immunoglobulin superfamily that functions as an inhibitory receptor in human NK cells. Eur J Immunol 29(10):3148–3159

    Article  CAS  PubMed  Google Scholar 

  56. Lankry D, Rovis TL, Jonjic S, Mandelboim O (2013) The interaction between CD300a and phosphatidylserine inhibits tumor cell killing by NK cells. Eur J Immunol 43(8):2151–2161

    Article  CAS  PubMed  Google Scholar 

  57. Sloma I, Jiang X, Eaves AC, Eaves CJ (2010) Insights into the stem cells of chronic myeloid leukemia. Leukemia 24(11):1823–1833

    Article  CAS  PubMed  Google Scholar 

  58. Horton SJ, Huntly BJ (2012) Recent advances in acute myeloid leukemia stem cell biology. Haematologica 97(7):966–974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. O’Brien JA, Rizzieri DA (2013) Leukemic stem cells: a review. Cancer Invest 31(4):215–220

    Article  PubMed  CAS  Google Scholar 

  60. Wiseman DH, Greystoke BF, Somervaille TC (2014) The variety of leukemic stem cells in myeloid malignancy. Oncogene 33(24):3091–3098

    Article  CAS  PubMed  Google Scholar 

  61. Costello RT, Fauriat C, Sivori S, Marcenaro E, Olive D (2004) NK cells: innate immunity against hematological malignancies? Trends Immunol 25(6):328–333

    Article  CAS  PubMed  Google Scholar 

  62. Carlsten M, Baumann BC, Simonsson M, Jadersten M, Forsblom AM, Hammarstedt C, Bryceson YT, Ljunggren HG, Hellstrom-Lindberg E, Malmberg KJ (2010) Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34 + blasts in myelodysplastic syndrome. Leukemia 24(9):1607–1616

    Article  CAS  PubMed  Google Scholar 

  63. Stringaris K, Sekine T, Khoder A, Alsuliman A, Razzaghi B, Sargeant R, Pavlu J, Brisley G, de Lavallade H, Sarvaria A, Marin D, Mielke S, Apperley JF, Shpall EJ, Barrett AJ, Rezvani K (2014) Leukemia-induced phenotypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia. Haematologica 99(5):836–847

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Curti A, Trabanelli S, Salvestrini V, Baccarani M, Lemoli RM (2009) The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology. Blood 113(11):2394–2401

    Article  CAS  PubMed  Google Scholar 

  65. Szczepanski MJ, Szajnik M, Welsh A, Whiteside TL, Boyiadzis M (2011) Blast-derived microvesicles in sera from patients with acute myeloid leukemia suppress natural killer cell function via membrane-associated transforming growth factor-beta1. Haematologica 96(9):1302–1309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ayala F, Dewar R, Kieran M, Kalluri R (2009) Contribution of bone microenvironment to leukemogenesis and leukemia progression. Leukemia 23(12):2233–2241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mussai F, De Santo C, Abu-Dayyeh I, Booth S, Quek L, McEwen-Smith RM, Qureshi A, Dazzi F, Vyas P, Cerundolo V (2013) Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment. Blood 122(5):749–758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Duan CW, Shi J, Chen J, Wang B, Yu YH, Qin X, Zhou XC, Cai YJ, Li ZQ, Zhang F, Yin MZ, Tao Y, Mi JQ, Li LH, Enver T, Chen GQ, Hong DL (2014) Leukemia propagating cells rebuild an evolving niche in response to therapy. Cancer Cell 25(6):778–793

    Article  CAS  PubMed  Google Scholar 

  69. Tsimberidou AM, Estey E, Wen S, Pierce S, Kantarjian H, Albitar M, Kurzrock R (2008) The prognostic significance of cytokine levels in newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndromes. Cancer 113(7):1605–1613

    Article  PubMed  Google Scholar 

  70. Kornblau SM, McCue D, Singh N, Chen W, Estrov Z, Coombes KR (2010) Recurrent expression signatures of cytokines and chemokines are present and are independently prognostic in acute myelogenous leukemia and myelodysplasia. Blood 116(20):4251–4261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Vitale C, Ambrosini P, Montaldo E, Ballerini F, Moretta L, Mingari MC (2015) IL-1beta-releasing human acute myeloid leukemia blasts modulate natural killer cell differentiation from CD34 + precursors. Haematologica 100(2):e42–e45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT et al (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313(23):1485–1492

    Article  CAS  PubMed  Google Scholar 

  73. Law TM, Motzer RJ, Mazumdar M, Sell KW, Walther PJ, O’Connell M, Khan A, Vlamis V, Vogelzang NJ, Bajorin DF (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(5):824–832

    Article  CAS  PubMed  Google Scholar 

  74. Bordignon C, Carlo-Stella C, Colombo MP, De Vincentiis A, Lanata L, Lemoli RM, Locatelli F, Olivieri A, Rondelli D, Zanon P, Tura S (1999) Cell therapy: achievements and perspectives. Haematologica 84(12):1110–1149

    CAS  PubMed  Google Scholar 

  75. Cheng M, Chen Y, Xiao W, Sun R, Tian Z (2013) NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol 10(3):230–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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(19):6287–6297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, McKenna D, Le C, Defor TE, Burns LJ, Orchard PJ, Blazar BR, Wagner JE, Slungaard A, Weisdorf DJ, Okazaki IJ, McGlave PB (2005) Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105(8):3051–3057

    Article  CAS  PubMed  Google Scholar 

  78. Geller MA, Cooley S, Judson PL, Ghebre R, Carson LF, Argenta PA, Jonson AL, Panoskaltsis-Mortari A, Curtsinger J, McKenna D, Dusenbery K, Bliss R, Downs LS, Miller JS (2011) A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy 13(1):98–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 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(12):1781–1789

    Article  PubMed  Google Scholar 

  80. Wennerberg E, Kremer V, Childs R, Lundqvist A (2015) CXCL10-induced migration of adoptively transferred human natural killer cells toward solid tumors causes regression of tumor growth in vivo. Cancer Immunol Immunother 64(2):225–235

    Article  CAS  PubMed  Google Scholar 

  81. Moustaki A, Argyropoulos KV, Baxevanis CN, Papamichail M, Perez SA (2011) Effect of the simultaneous administration of glucocorticoids and IL-15 on human NK cell phenotype, proliferation and function. Cancer Immunol Immunother 60(12):1683–1695

    Article  CAS  PubMed  Google Scholar 

  82. Vacca P, Martini S, Garelli V, Passalacqua G, Moretta L, Mingari MC (2013) NK cells from malignant pleural effusions are not anergic but produce cytokines and display strong antitumor activity on short-term IL-2 activation. Eur J Immunol 43(2):550–561

    Article  CAS  PubMed  Google Scholar 

  83. Vacca P, Martini S, Mingari MC, Moretta L (2013) NK cells from malignant pleural effusions are potent antitumor effectors: a clue for adoptive immunotherapy? Oncoimmunology 2(4):e23638

    Article  PubMed  PubMed Central  Google Scholar 

  84. Terme M, Fridman WH, Tartour E (2013) NK cells from pleural effusions are potent antitumor effector cells. Eur J Immunol 43(2):331–334

    Article  CAS  PubMed  Google Scholar 

  85. Ni J, Miller M, Stojanovic A, Garbi N, Cerwenka A (2012) Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. J Exp Med 209(13):2351–2365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ardolino M, Azimi CS, Iannello A, Trevino TN, Horan L, Zhang L, Deng W, Ring AM, Fischer S, Garcia KC, Raulet DH (2014) Cytokine therapy reverses NK cell anergy in MHC-deficient tumors. J Clin Invest 124(11):4781–4794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Vacchelli E, Galluzzi L, Eggermont A, Galon J, Tartour E, Zitvogel L, Kroemer G (2012) Trial watch: immunostimulatory cytokines. Oncoimmunology 1(4):493–506

    Article  PubMed  PubMed Central  Google Scholar 

  88. Tarhini AA, Millward M, Mainwaring P, Kefford R, Logan T, Pavlick A, Kathman SJ, Laubscher KH, Dar MM, Kirkwood JM (2009) A phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma. Cancer 115(4):859–868

    Article  CAS  PubMed  Google Scholar 

  89. Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, Fleisher TA, Dubois SP, Perera LP, Stewart DM, Goldman CK, Bryant BR, Decker JM, Chen J, Worthy TA, Figg WD Sr, Peer CJ, Sneller MC, Lane HC, Yovandich JL, Creekmore SP, Roederer M, Waldmann TA (2015) Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J Clin Oncol 33(1):74–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Terme M, Ullrich E, Delahaye NF, Chaput N, Zitvogel L (2008) Natural killer cell-directed therapies: moving from unexpected results to successful strategies. Nat Immunol 9(5):486–494

    Article  CAS  PubMed  Google Scholar 

  91. Krieg S, Ullrich E (2012) Novel immune modulators used in hematology: impact on NK cells. Front Immunol 3:388

    PubMed  PubMed Central  Google Scholar 

  92. Romagne F, Andre P, Spee P, Zahn S, Anfossi N, Gauthier L, Capanni M, Ruggeri L, Benson DM Jr, Blaser BW, Della Chiesa M, Moretta A, Vivier E, Caligiuri MA, Velardi A, Wagtmann N (2009) Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood 114(13):2667–2677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kohrt HE, Thielens A, Marabelle A, Sagiv-Barfi I, Sola C, Chanuc F, Fuseri N, Bonnafous C, Czerwinski D, Rajapaksa A, Waller E, Ugolini S, Vivier E, Romagne F, Levy R, Blery M, Andre P (2014) Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies. Blood 123(5):678–686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Oberoi P, Wels WS (2013) Arming NK cells with enhanced antitumor activity: CARs and beyond. Oncoimmunology 2(8):e25220

    Article  PubMed  PubMed Central  Google Scholar 

  95. Reisner Y, Kapoor N, Kirkpatrick D, Pollack MS, Cunningham-Rundles S, Dupont B, Hodes MZ, Good RA, O’Reilly RJ (1983) Transplantation for severe combined immunodeficiency with HLA-A, B, D, DR incompatible parental marrow cells fractionated by soybean agglutinin and sheep red blood cells. Blood 61(2):341–348

    CAS  PubMed  Google Scholar 

  96. Locatelli F, Merli P, Rutella S (2013) At the bedside: innate immunity as an immunotherapy tool for hematological malignancies. J Leukoc Biol 94(6):1141–1157

    Article  PubMed  CAS  Google Scholar 

  97. Aversa F, Tabilio A, Terenzi A, Velardi A, Falzetti F, Giannoni C, Iacucci R, Zei T, Martelli MP, Gambelunghe C et al (1994) Successful engraftment of T-cell-depleted haploidentical “three-loci” incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood 84(11):3948–3955

    CAS  PubMed  Google Scholar 

  98. Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F, Ruggeri L, Barbabietola G, Aristei C, Latini P, Reisner Y, Martelli MF (1998) Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 339(17):1186–1193

    Article  CAS  PubMed  Google Scholar 

  99. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295(5562):2097–2100

    Article  CAS  PubMed  Google Scholar 

  100. Moretta L, Locatelli F, Pende D, Marcenaro E, Mingari MC, Moretta A (2011) Killer Ig-like receptor-mediated control of natural killer cell alloreactivity in haploidentical hematopoietic stem cell transplantation. Blood 117(3):764–771

    Article  CAS  PubMed  Google Scholar 

  101. Locatelli F, Pende D, Mingari MC, Bertaina A, Falco M, Moretta A, Moretta L (2013) Cellular and molecular basis of haploidentical hematopoietic stem cell transplantation in the successful treatment of high-risk leukemias: role of alloreactive NK cells. Front Immunol 4:15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Pende D, Bottino C, Castriconi R, Cantoni C, Marcenaro S, Rivera P, Spaggiari GM, Dondero A, Carnemolla B, Reymond N, Mingari MC, Lopez M, Moretta L, Moretta A (2005) PVR (CD155) and nectin-2 (CD112) as ligands of the human DNAM-1 (CD226) activating receptor: involvement in tumor cell lysis. Mol Immunol 42(4):463–469

    Article  CAS  PubMed  Google Scholar 

  103. Pende D, Marcenaro S, Falco M, Martini S, Bernardo ME, Montagna D, Romeo E, Cognet C, Martinetti M, Maccario R, Mingari MC, Vivier E, Moretta L, Locatelli F, Moretta A (2009) Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity. Blood 113(13):3119–3129

    Article  CAS  PubMed  Google Scholar 

  104. Pende D, Spaggiari GM, Marcenaro S, Martini S, Rivera P, Capobianco A, Falco M, Lanino E, Pierri I, Zambello R, Bacigalupo A, Mingari MC, Moretta A, Moretta L (2005) Analysis of the receptor-ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the poliovirus receptor (CD155) and nectin-2 (CD112). Blood 105(5):2066–2073

    Article  CAS  PubMed  Google Scholar 

  105. Chewning JH, Gudme CN, Hsu KC, Selvakumar A, Dupont B (2007) KIR2DS1-positive NK cells mediate alloresponse against the C2 HLA-KIR ligand group in vitro. J Immunol 179(2):854–868

    Article  CAS  PubMed  Google Scholar 

  106. Venstrom JM, Pittari G, Gooley TA, Chewning JH, Spellman S, Haagenson M, Gallagher MM, Malkki M, Petersdorf E, Dupont B, Hsu KC (2012) HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1. N Engl J Med 367(9):805–816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Symons HJ, Leffell MS, Rossiter ND, Zahurak M, Jones RJ, Fuchs EJ (2010) Improved survival with inhibitory killer immunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors after nonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant 16(4):533–542

    Article  PubMed  PubMed Central  Google Scholar 

  108. Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Le CT, Marsh SG, Geraghty D, Spellman S, Haagenson MD, Ladner M, Trachtenberg E, Parham P, Miller JS (2010) Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood 116(14):2411–2419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Oevermann L, Michaelis SU, Mezger M, Lang P, Toporski J, Bertaina A, Zecca M, Moretta L, Locatelli F, Handgretinger R (2014) KIR B haplotype donors confer a reduced risk for relapse after haploidentical transplantation in children with ALL. Blood 124(17):2744–2747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Stern M, Ruggeri L, Mancusi A, Bernardo ME, de Angelis C, Bucher C, Locatelli F, Aversa F, Velardi A (2008) Survival after T cell-depleted haploidentical stem cell transplantation is improved using the mother as donor. Blood 112(7):2990–2995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ichinohe T, Teshima T, Matsuoka K, Maruya E, Saji H (2005) Fetal-maternal microchimerism: impact on hematopoietic stem cell transplantation. Curr Opin Immunol 17(5):546–552

    Article  CAS  PubMed  Google Scholar 

  112. Dutta P, Burlingham WJ (2009) Tolerance to noninherited maternal antigens in mice and humans. Curr Opin Organ Transplant 14(4):439–447

    Article  PubMed  PubMed Central  Google Scholar 

  113. Handgretinger R (2012) New approaches to graft engineering for haploidentical bone marrow transplantation. Semin Oncol 39(6):664–673

    Article  CAS  PubMed  Google Scholar 

  114. Locatelli F, Moretta F, Brescia L, Merli P (2014) Natural killer cells in the treatment of high-risk acute leukaemia. Semin Immunol 26(2):173–179

    Article  CAS  PubMed  Google Scholar 

  115. Norell H, Moretta A, Silva-Santos B, Moretta L (2013) At the bench: preclinical rationale for exploiting NK cells and gammadelta T lymphocytes for the treatment of high-risk leukemias. J Leukoc Biol 94(6):1123–1139

    Article  PubMed  CAS  Google Scholar 

  116. Airoldi I, Bertaina A, Prigione I, Zorzoli A, Pagliara D, Cocco C, Meazza R, Loiacono F, Lucarelli B, Bernardo ME, Barbarito G, Pende D, Moretta A, Pistoia V, Moretta L, Locatelli F (2015) gammadelta T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-alphabeta +/CD19 + lymphocytes. Blood 125(15):2349–2358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Bertaina A, Merli P, Rutella S, Pagliara D, Bernardo ME, Masetti R, Pende D, Falco M, Handgretinger R, Moretta F, Lucarelli B, Brescia LP, Li Pira G, Testi M, Cancrini C, Kabbara N, Carsetti R, Finocchi A, Moretta A, Moretta L, Locatelli F (2014) HLA-haploidentical stem cell transplantation after removal of alphabeta + T and B cells in children with nonmalignant disorders. Blood 124(5):822–826

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Grants awarded by Associazione Italiana Ricerca sul Cancro (AIRC): IG 2010 project n. 10225 (to L. Moretta), IG 2014 project n. 15283 (to L. Moretta) and “Special Program Molecular Clinical Oncology 5 × 1000” project n. 9962 (to L. Moretta). This work was also supported by Italian Ministry of Health Grants RF-2010-2316606 (to F. Locatelli, L. Moretta and D. Pende) and RF-2010-2316319 (to D. Pende).

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Authors and Affiliations

  1. IRCCS AOU San Martino-IST, Genoa, Italy

    Gabriella Pietra, Chiara Vitale, Daniela Pende & Maria Cristina Mingari

  2. Department of Experimental Medicine, University of Genova, Genoa, Italy

    Gabriella Pietra, Chiara Vitale, Paola Vacca, Claudia Cantoni, Maria Cristina Mingari & Alessandro Moretta

  3. IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy

    Alice Bertaina, Franco Locatelli & Lorenzo Moretta

  4. Department of Medicine, University of Verona, Verona, Italy

    Francesca Moretta

  5. Ospedale Sacro Cuore, Negrar, Verona, Italy

    Francesca Moretta

  6. Istituto Giannina Gaslini, Via G. Gaslini n. 5, 16147, Genoa, Italy

    Michela Falco, Elisa Montaldo & Claudia Cantoni

  7. Center of Excellence for Biomedical Research, University of Genova, Genoa, Italy

    Claudia Cantoni, Maria Cristina Mingari & Alessandro Moretta

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  1. Gabriella Pietra
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  2. Chiara Vitale
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  3. Daniela Pende
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  4. Alice Bertaina
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  7. Paola Vacca
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  11. Alessandro Moretta
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  12. Franco Locatelli
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  13. Lorenzo Moretta
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Correspondence to Lorenzo Moretta.

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This article is part of the Symposium-in-Writing “Natural killer cells, ageing and cancer”, a series of papers published in Cancer Immunology, Immunotherapy.

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Pietra, G., Vitale, C., Pende, D. et al. Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias. Cancer Immunol Immunother 65, 465–476 (2016). https://doi.org/10.1007/s00262-015-1744-y

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