Impairment of NK Cell Mediated Immune Surveillance Against Acute Myeloid Leukemia

Natural killer (NK) cells are cytotoxic lymphocytes contributing in innate immune responses that recog- nize and kill virus-infected and tumor cells without prior stimulation. Several clinical trials have indicat- ed that NK cell-based immunotherapy represents a promising antitumor immunotherapeutic approach due to their key role in mediating graft versus leukemic effect against hematological malignancies, par- ticularly acute myeloid leukemia. However, the antitumor activity of NK cells is inhibited as a result to immune-evasion mechanisms developed by malignant cells through alterations in the expression of activating and inhibitory receptors and their ligands, as well as secretion of soluble NK-inhibitory mediators. Until now, the exact molecular mechanisms involved in these alterations are still not defined.

PDF

___

1. Caligiuri MA. Human natural killer cells. Blood 2008;112(3):461–9.
2. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol 2008;9(5):503–10.
3. Moretta L, Bottino C, Pende D, Vitale M, Mingari MC, Moretta A. Human natural killer cells: Molecular mechanisms controlling NK cell activation and tumor cell lysis. Immunol Lett 2005;100(1):7–13.
4. Miller JS, Cooley S, Parham P, Farag SS, Verneris MR, McQueen KL, et al. Missing KIR ligands are associ- ated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT. Blood 2007;109(11):5058–61.
5. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlom- chik WD, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002;295(5562):2097–100.
6. Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol 2001;22(11):633–40.
7. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive im- munity? The example of natural killer cells. Science 2011;331(6013):44–9.
8. Vivier E. What is natural in natural killer cells? Im- munol Lett 2006; 107(1):1–7.
9. Assarsson E, Kambayashi T, Persson CM, Ljunggren H-G, Chambers BJ. 2B4 co-stimulation: NK cells and their control of adaptive immune responses. Mol Im- munol 2005;42(4):419–23.
10. Kalinski P, Giermasz A, Nakamura Y, Basse P, Storkus WJ, Kirkwood JM, et al. Helper role of NK cells dur- ing the induction of anticancer responses by dendritic cells. Mol Immunol 2005;42(4):535–9.
11. Smyth MJ, Cretney E, Kelly JM, Westwood JA, Street SEA, Yagita H, et al. Activation of NK cell cytotoxicity. Mol Immunol 2005;42(4):501–10.
12. Long EO, Sik Kim H, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Im- munol 2013;31(1):227–58.
13. Vivier E, Ugolini S, Blaise D, Chabannon C, Brossay L. Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol 2012;12(4):239–52.
14. Fang F, Xiao W, Tian Z. NK cell-based immunother- apy for cancer. Semin Immunol 2017;31:37–54.
15. Chavez-Galan L, Arenas-Del Angel MC, Zenteno E, Chavez R, Lascurain R. Cell death mechanisms in- duced by cytotoxic lymphocytes. Cell Mol Immunol 2009;6(1):15–25.
16. Estey E, Döhner H. Acute myeloid leukaemia. The Lancet 2006;368(9550):1894–907.
17. Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid leukemia. Blood 2005;106(4):1154–63.
18. Barrett AJ, Le Blanc K. Immunotherapy prospects for acute myeloid leukaemia. Clin Exp Immunol 2010;161(2):223–32.
19. Lichtenegger FS, Krupka C, Köhnke T, Subklewe M. Immunotherapy for acute myeloid leukemia. Semin Hematol 2015;52(3):207–14.
20. Tang X, Yang L, Li Z, Nalin AP, Dai H, Xu T, et al. First- in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. Am J Cancer Res 2018;8(6):1083–9.
21. Dolstra H, Roeven MWH, Spanholtz J, Hangalapura BN, Tordoir M, Maas F, et al. Successful transfer of umbilical cord blood CD34+ hematopoietic stem and progenitor-derived NK cells in older acute myeloid leukemia patients. Clin Cancer Res Off J Am Assoc Cancer Res 2017;23(15):4107–18.
22. Boyiadzis M, Agha M, Redner RL, Sehgal A, Im A, Hou J-Z, et al. Phase 1 clinical trial of adoptive immunother- apy using “off-the-shelf ” activated natural killer cells in patients with refractory and relapsed acute myeloid leukemia. Cytotherapy 2017;19(10):1225–32.
23. Cooley S, He F, Bachanova V, Vercellotti GM, DeFor TE, Curtsinger JM, et al. First-in-human trial of rhIL-15 and haploidentical natural killer cell ther- apy for advanced acute myeloid leukemia. Blood Adv 2019;3(13):1970–80.
24. Fehniger TA, Miller JS, Stuart RK, Cooley S, Salho- tra A, Curtsinger J, et al. A phase 1 trial of CNDO- 109-activated natural killer cells in patients with high-risk acute myeloid leukemia. Biol Blood Mar- row Transplant J Am Soc Blood Marrow Transplant 2018;24(8):1581–9.
25. Bachanova V, Cooley S, Defor TE, Verneris MR, Zhang B, McKenna DH, et al. Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion pro- tein. Blood 2014;123(25):3855–63.
26. Carlsten M, Järås M. Natural killer cells in myeloid malignancies: immune surveillance, NK cell dysfunc- tion, and pharmacological opportunities to bolster the endogenous NK cells. Front Immunol 2019;10:2357.
27. Xu J, Niu T. Natural killer cell-based immunotherapy for acute myeloid leukemia. J Hematol OncolJ Hema- tol Oncol 2020;13(1):167.
28. Costello RT, Sivori S, Marcenaro E, Lafage-Pochitaloff M, Mozziconacci M-J, Reviron D, et al. Defective ex- pression and function of natural killer cell–triggering receptors in patients with acute myeloid leukemia. Blood 2002;99(10):3661–7.
29. De Maria A, Fogli M, Costa P, Murdaca G, Puppo F, Mavilio D, et al. The impaired NK cell cytolytic func- tion in viremic HIV-1 infection is associated with a reduced surface expression of natural cytotoxicity re- ceptors (NKp46, NKp30 and NKp44). Eur J Immunol 2003;33(9):2410–8.
30. Fauriat C, Just-Landi S, Mallet F, Arnoulet C, Sainty D, Olive D, et al. Deficient expression of NCR in NK cells from acute myeloid leukemia: evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction. Blood 2007;109(1):323–30.
31. Stringaris K, Sekine T, Khoder A, Alsuliman A, Raz- zaghi B, Sargeant R, et al. Leukemia-induced phe- notypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia. Haematologica 2014;99(5):836–47.
32. Venton G, Labiad Y, Colle J, Fino A, Afridi S, Torres M, et al. Natural killer cells in acute myeloid leukemia patients: from phenotype to transcriptomic analysis. Immunol Res 2016;64(5–6):1225–36.
33. Khaznadar Z, Boissel N, Agaugué S, Henry G, Cheok M, Vignon M, et al. Defective NK cells in acute myeloid leukemia patients at diagnosis are associated with blast transcriptional signatures of immune eva- sion. J Immunol 2015;195(6):2580–90.
34. Sanchez-Correa B, Morgado S, Gayoso I, Bergua JM, Casado JG, Arcos MJ, et al. Human NK cells in acute myeloid leukaemia patients: analysis of NK cell-acti- vating receptors and their ligands. Cancer Immunol Immunother CII 2011;60(8):1195–205.
35. Szczepanski MJ, Szajnik M, Welsh A, Foon KA, Whiteside TL, Boyiadzis M. Interleukin-15 enhances natural killer cell cytotoxicity in patients with acute myeloid leukemia by upregulating the activating NK cell receptors. Cancer Immunol Immunother CII 2010;59(1):73–9.
36. Chretien A-S, Devillier R, Fauriat C, Orlanducci F, Harbi S, Le Roy A, et al. NKp46 expression on NK cells as a prognostic and predictive biomarker for response to allo-SCT in patients with AML. OncoImmunology 2017;6(12):e1307491.
37. Diermayr S, Himmelreich H, Durovic B, Mathys-Sch- neeberger A, Siegler U, Langenkamp U, et al. NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to al- lorecognition by NK-cell lines with single KIR-HLA class I specificities. Blood 2008;111(3):1428–36.
38. Nowbakht P, Ionescu M-CS, Rohner A, Kalberer CP, Rossy E, Mori L, et al. Ligands for natural killer cell- activating receptors are expressed upon the matura- tion of normal myelomonocytic cells but at low levels in acute myeloid leukemias. Blood 2005;105(9):3615– 22.
39. Pende D, Spaggiari GM, Marcenaro S, Martini S, Rivera P, Capobianco A, et al. Analysis of the recep- tor-ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the Po- liovirus receptor (CD155) and Nectin-2 (CD112). Blood 2005;105(5):2066–73.
40. Salih HR, Antropius H, Gieseke F, Lutz SZ, Kanz L, Rammensee H-G, et al. Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood 2003;102(4):1389–96.
41. Hilpert J, Grosse-Hovest L, Grünebach F, Buechele C, Nuebling T, Raum T, et al. Comprehensive analysis of NKG2D ligand expression and release in leukemia: implications for NKG2D-mediated NK cell responses. J Immunol 2012;189(3):1360–71.
42. Kearney CJ, Ramsbottom KM, Voskoboinik I, Darcy PK, Oliaro J. Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing. Oncoimmunology 2016;5(8):e1196308.
43. Sanchez-Correa B, Gayoso I, Bergua JM, Casado JG, Morgado S, Solana R, et al. Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients. Immunol Cell Biol 2012;90(1):109–15.
44. Chretien A-S, Fauriat C, Orlanducci F, Galseran C, Rey J, Bouvier Borg G, et al. Natural killer defective matu- ration is associated with adverse clinical outcome in patients with acute myeloid leukemia. Front Immunol 2017;8:1–11.
45. Leong JW, Sullivan RP, Fehniger TA. microRNA man- agement of NK cell developmental and functional pro- grams. Eur J Immunol 2014;44(10):2862–8.
46. Marcucci G, Mrózek K, Radmacher MD, Garzon R, Bloomfield CD. The prognostic and functional role of microRNAs in acute myeloid leukemia. Blood 2011;117(4):1121–9.
47. Wallace JA, O’Connell RM. MicroRNAs and acute myeloid leukemia: therapeutic implications and emerging concepts. Blood 2017;130(11):1290–301.
48. Mundy-Bosse BL, Scoville SD, Chen L, McConnell K, Mao HC, Ahmed EH, et al. MicroRNA-29b me- diates altered innate immune development in acute leukemia. J Clin Invest 2016;126(12):4404–16.
49. Wang Z, Xiao Y, Guan W, Wang M, Chen J, Zhang L, et al. Acute myeloid leukemia immune escape by epi- genetic CD48 silencing. Clin Sci 2020;134(2):261–71.
50. Baessler T, Krusch M, Schmiedel BJ, Kloss M, Baltz KM, Wacker A, et al. Glucocorticoid-induced tumor necrosis factor receptor-related protein ligand sub- verts immunosurveillance of acute myeloid leukemia in humans. Cancer Res 2009;69(3):1037–45.
51. Baessler T, Charton JE, Schmiedel BJ, Grünebach F, Krusch M, Wacker A, et al. CD137 ligand mediates opposite effects in human and mouse NK cells and im- pairs NK-cell reactivity against human acute myeloid leukemia cells. Blood 2010;115(15):3058–69.
52. Baginska J, Viry E, Paggetti J, Medves S, Berchem G, Moussay E, et al. The critical role of the tumor microen- vironment in shaping natural killer cell-mediated anti- tumor immunity. Front Immunol 2013;4:490.
53. Otegbeye F, Ojo E, Moreton S, Mackowski N, Lee DA, Lima M de, et al. Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro ex- panded natural killer cells in AML and colon cancer models. PLOS ONE 2018;13(1):e0191358.
54. Fauriat C. Defective killing of dendritic cells by autol- ogous natural killer cells from acute myeloid leukemia patients. Blood 2005;106(6):2186–8.
55. Shenghui Z, Yixiang H, Jianbo W, Kang Y, Laixi B, Yan Z, et al. Elevated frequencies of CD4+ CD25+ CD127lo regulatory T cells is associated to poor prog- nosis in patients with acute myeloid leukemia. Int J Cancer 2011;129(6):1373–81.
56. Chiossone L, Vienne M, Kerdiles YM, Vivier E. Natural killer cell immunotherapies against cancer: checkpoint inhibitors and more. Semin Immunol 2017;31:55–63.
57. Gauthier M, Laroye C, Bensoussan D, Boura C, De- cot V. Natural Killer cells and monoclonal antibodies: Two partners for successful antibody dependent cyto- toxicity against tumor cells. Crit Rev Oncol Hematol 2021;160:103261.
58. Lamb MG, Rangarajan HG, Tullius BP, Lee DA. Nat- ural killer cell therapy for hematologic malignancies: successes, challenges, and the future. Stem Cell Res Ther 2021;12(1):211.
59. Mehta RS, Randolph B, Daher M, Rezvani K. NK cell therapy for hematologic malignancies. Int J Hematol 2018;107(3):262–70.
60. Torelli GF, Guarini A, Palmieri G, Breccia M, Vitale A, Santoni A, et al. Expansion of cytotoxic effectors with lytic activity against autologous blasts from acute myeloid leukaemia patients in complete haematolog- ical remission: autologous killing of aml blasts by ex- panded NK cells. Br J Haematol 2002;116(2):299–307.
61. Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, et al. Observations on the sys- temic administration of autologous lymphokine-ac- tivated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 1985;313(23):1485–92.
62. Wrangle JM, Patterson A, Johnson CB, Neitzke DJ, Mehrotra S, Denlinger CE, et al. IL-2 and beyond in cancer immunotherapy. J Interferon Cytokine Res 2018;38(2):45–68.
63. Floros T, Tarhini AA. Anticancer cytokines: biology and clinical effects of interferon-α2, interleukin (IL)-2, IL-15, IL-21, and IL-12. Semin Oncol 2015;42(4):539– 48.
64. Sanchez-Correa B, Bergua JM, Pera A, Campos C, Arcos MJ, Bañas H, et al. In vitro culture with inter- leukin-15 leads to expression of activating receptors and recovery of natural killer cell function in acute myeloid leukemia patients. Front Immunol 2017;8:931.
65. Busfield SJ, Biondo M, Wong M, Ramshaw HS, Lee EM, Ghosh S, et al. Targeting of acute myeloid leukemia in vitro and in vivo with an anti-CD123 mAb engineered for optimal ADCC. Leukemia 2014;28(11):2213–21.
66. Lee EM, Yee D, Busfield SJ, McManus JF, Cummings N, Vairo G, et al. Efficacy of an Fc-modified anti- CD123 antibody (CSL362) combined with chemo- therapy in xenograft models of acute myelogenous leukemia in immunodeficient mice. Haematologica 2015;100(7):914–26.
67. Koerner SP, André MC, Leibold JS, Kousis PC, Kübler A, Pal M, et al. An Fc-optimized CD133 antibody for induction of NK cell reactivity against myeloid leukemia. Leukemia 2017;31(2):459–69.
68. Mamessier E, Sylvain A, Thibult M-L, Houvenaeghel G, Jacquemier J, Castellano R, et al. Human breast cancer cells enhance self-tolerance by promoting eva- sion from NK cell antitumor immunity. J Clin Invest 2011;121(9):3609–22.
69. Sheu B-C, Chiou S-H, Lin H-H, Chow S-N, Huang S-C, Ho H-N, et al. Up-regulation of inhibitory nat- ural killer receptors CD94/NKG2A with suppressed intracellular perforin expression of tumor-infiltrating CD8+ T lymphocytes in human cervical carcinoma. Cancer Res 2005;65(7):2921–9.
70. André P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T, et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by un- leashing both T and NK cells. Cell 2018;175(7):1731– 43.e13.
71. Ruggeri L, Urbani E, Andre P, Mancusi A, Tosti A, Topini F, et al. Effects of anti-NKG2A antibody admin- istration on leukemia and normal hematopoietic cells. Haematologica 2016;101(5):626–33.
72. Davis Z, Felices M, Lenvik TR, Badal S, Hinderlie P, Blazar BR, et al. PD-1 is expressed at low levels on all peripheral blood natural killer cells but is a signifi- cant suppressor of NK function against PD-1 ligand expressing tumor targets. Blood 2019;134(Supple- ment_1):621.
73. Pesce S, Greppi M, Tabellini G, Rampinelli F, Parolini S, Olive D, et al. Identification of a subset of human nat- ural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization. J Allergy Clin Immunol 2017;139(1):335–46.e3.
74. Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Da- vanlou M, Geng Q-R, et al. Expression of PD-L1, PD- L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 2014;28(6):1280–8.
75. Romero D. Immunotherapy: PD-1 says goodbye, TIM- 3 says hello. Nat Rev Clin Oncol 2016;13(4):202–3.
76. Guo Y, Feng X, Jiang Y, Shi X, Xing X, Liu X, et al. PD1 blockade enhances cytotoxicity of in vitro expanded natural killer cells towards myeloma cells. Oncotarget 2016;7(30):48360–74.
77. Liu Y, Cheng Y, Xu Y, Wang Z, Du X, Li C, et al. In- creased expression of programmed cell death protein 1 on NK cells inhibits NK-cell-mediated anti-tumor function and indicates poor prognosis in digestive cancers. Oncogene 2017;36(44):6143–53.
78. Ravandi F, Assi R, Daver N, Benton CB, Kadia T, Thompson PA, et al. Idarubicin, cytarabine, and nivolumab in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syn- drome: a single-arm, phase 2 study. Lancet Haematol 2019;6(9):e480–8.
79. Ruggeri L, Mancusi A, Burchielli E, Aversa F, Martelli MF, Velardi A. Natural killer cell alloreactivity in allo- geneic hematopoietic transplantation. Curr Opin On- col 2007;19(2):142–7.
80. Suck G, Linn YC, Tonn T. Natural killer cells for therapy of leukemia. Transfus Med Hemotherapy 2016;43(2):89–95.
81. Knorr DA, Bachanova V, Verneris MR, Miller JS. Clin- ical utility of natural killer cells in cancer therapy and transplantation. Semin Immunol 2014;26(2):161–72.
82. Choi I, Yoon SR, Park S-Y, Kim H, Jung S-J, Jang YJ, et al. Donor-derived natural killer cells infused after human leukocyte antigen–haploidentical hematopoi- etic cell transplantation: a dose-escalation study. Biol Blood Marrow Transplant 2014;20(5):696–704.
83. Devillier R, Calmels B, Guia S, Taha M, Fauriat C, Mfarrej B, et al. Phase I trial of prophylactic donor- derived IL-2-activated NK cell infusion after allo- geneic hematopoietic stem cell transplantation from a matched sibling donor. Cancers 2021;13(11):2673