Phenotypic and functional changes of NK cells in patients with myelodysplastic syndrome and acute myeloid leukemia treated with hypomethylating drugs

Natural killer cells (NK cells) are cytotoxic lymphocytes that play a pivotal role in maintaining immunological surveillance and in developing an innate immune response. Since the discovery of NK cells in 1973, the mechanisms of their functioning have been studied in details, and there is currently no doubt that they play a special role in the process of recognition and destruction of transformed and malignant cells. Understanding the role of NK cells in antitumor immunity, on the one hand, leads to emergence of new immunotherapeutic strategies and, on the other hand, allows to adjust the existing treatment regimens for tumor diseases, in accordance with the principle of primum non nocere. Optimization of cancer therapy protocols executed in order to protect immune cells from death and functional impairment is an important problem that cannot be successfully resolved without regular aggregation of the results from disparate studies and critical analysis of the all accumulated data.

The objective of this review is to create a relevant and holistic picture of changes in the phenotypic and functional characteristics of NK cells in patients with two related hematological diseases – myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). For the treatment of both illnesses, drugs from the group of hypomethylating agents are used, the acting mechanism of which, unlike classical cytostatic agents, is based on modulation of the tumor cell genes expression. All the cells of the body are being affected, including NK cells, since these drugs act nonspecifically. Such an interaction leads to a hypomethylation of NK cell DNA and changes the expression of functional receptors, which, in turn, provide the development of antitumor NK cell immune response.

Of course, just the fact of changing gene expression in certain cells does not allow us to fully judge the drug’s impact on the state of immune system. Meanwhile, the origin of this change and its role are important in the context of the disease pathogenesis. Ultimately, a simple description of an increase or decrease in a single receptor expression is not illustrative, since it can lead to uncertain consequences. For this reason, the current review, in addition to describing the existing data on the changes of NK cell receptors expression under the influence of hypomethylating drugs, gives a special attention to critical analysis of functional characteristics of NK cells, including their cytotoxic activity aimed at malignant blast cells, being a determinant of clinical course in the described diseases. 

1. Almeida A.M., Ramos F. Acute myeloid leukemia in the older adults. Leuk. Res. Rep., 2016, Vol. 6, pp. 1-7.

2. Carrillo-Bustamante P., Kesmir C., de Boer R.J. The evolution of natural killer cell receptors. Immunogenetics, 2016, Vol. 68, no. 1, pp 3-18.

3. Chan H.W., Kurago Z.B., Stewart C.A. et al. DNA methylation maintains allele-specific KIR gene expression in human natural killer cells. J. Exp. Med., 2003, Vol. 197, no. 2, pp. 245-255.

4. Christman J.K. 5-Azacytidine and 5-aza-2’-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene, 2002, Vol. 21, no. 35, pp. 5483-5495.

5. Cogle C.R. Incidence and burden of the myelodysplastic syndromes. Curr. Hematol. Malig. Rep., 2015, Vol. 10, no. 3, pp. 272-281.

6. Dan H., Zhang S., Zhou Y., Guan Q. DNA Methyltransferase inhibitors: catalysts for antitumour immune responses. Onco Targets Ther., 2019, Vol. 12, pp. 10903-10916.

7. Daneshbod Y., Kohan L., Taghadosi V., Weinberg O.K., Arber D.A. Prognostic significance of complex karyotypes in acute myeloid leukemia. Curr. Treat. Options Oncol., 2019, Vol. 20, no. 2, 15. doi: 10.1007/s11864-019-0612-y.

8. Döhner H., Weisdorf D.J., Bloomfield C.D. Acute myeloid leukemia. N. Engl. J. Med., 2015, Vol. 373, no. 12, pp. 1136-1152.

9. Estey E.H. Acute myeloid leukemia: 2019 update on risk-stratification and management. Am. J. Hematol., 2018, Vol. 93, no. 10, pp. 1267-1291.

10. Fenaux P., Mufti G.J., Hellström-Lindberg E. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J. Clin. Oncol., 2010, Vol. 28, no. 4, pp. 562-569.

11. Gang A.O., Frosig T.M., Brimnes M.K. 5-Azacytidine treatment sensitizes tumor cells to T-cell mediated cytotoxicity and modulates NK cells in patients with myeloid malignancies. Blood Cancer J., 2014, Vol. 4, no. 3, e197. doi: 10.1038/bcj.2014.14.

12. Gao X.N., Lin J., Wang L.L., Yu L. Demethylating treatment suppresses natural killer cell cytolytic activity. Mol Immunol., 2009, Vol. 46, no. 10, pp. 2064-2070.

13. Gardin C., Dombret H. Hypomethylating agents as a therapy for AML. Curr. Hematol. Malig. Rep., 2017, Vol. 12, no. 1, pp. 1-10.

14. Gardiner C.M. NK cell metabolism. J. Leukoc. Biol., 2019, Vol. 105, no. 6, pp. 1235-1242.

15. Hoglund P., Brodin P. Current perspectives of natural killer cell education by MHC class I molecules. Nat. Rev. Immunol., 2010, Vol. 10, no. 10, pp. 724-734.

16. Horowitz A., Strauss-Albee D.M., Leipold M., Kubo J., Nemat-Gorgani N., Dogan O.C., Dekker C.L., Mackey S., Maecker H., Swan G.E., Davis M.M., Norman P.J., Guethlein L.A., Desai M., Parham P., Blish C.A. Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry. Sci. Transl. Med., 2013, Vol. 5, no. 208, 208ra145. doi: 10.1126/scitranslmed.3006702.

17. Hourigan C.S., Karp J.E. Development of therapeutic agents for older patients with acute myelogenous leukemia. Curr. Opin. Investig. Drugs, 2010, Vol. 11, no. 6, pp. 669-677.

18. Jacobs B., Tognarelli S., Poller K., Bader P., Mackensen A., Ullrich E. NK Cell subgroups, phenotype, and functions after autologous stem cell transplantation. Front. Immunol., 2015, Vol. 6, p. 583. doi: 10.3389/fimmu.2015.00583.

19. Kantarjian H.M., Issa J.P. Decitabine dosing schedules. Semin. Hematol., 2005, Vol. 42, no. 3, Suppl. 2, pp. S17-S22.

20. Kennedy J.A., Ebert B.L. Clinical implications of genetic mutations in myelodysplastic syndrome. J. Clin. Oncol., 2017, Vol. 35, no. 9, pp. 968-974.

21. Campbell K.S., Hasegawa J. Natural killer cell biology: an update and future directions. J. Allergy Clin. Immunol., 2013 Vol. 132, Iss. 3, pp. 536-544.

22. Koeffler H.P., Leong G. Preleukemia: one name, many meanings. Leukemia, 2017, Vol. 31, no. 3, pp. 534-542.

23. Kopp L.M., Ray A., Denman C.J., Senyukov V.S., Somanchi S.S., Zhu S., Lee D.A. Decitabine has a biphasic effect on natural killer cell viability, phenotype, and function under proliferative conditions. Mol. Immunol., 2013, Vol. 54, no. 3-4, pp. 296-301.

24. Kuykendall A., Duployez N., Boissel N., Lancet J.E., Welch J.S. Acute myeloid leukemia: the good, the bad, and the ugly. Am. Soc. Clin. Oncol. Educ. Book, 2018, Vol. 38 pp. 555-573.

25. Lindblad K.E., Goswami M., Hourigan C.S., Oetjen K.A. Immunological effects of hypomethylating agents. Expert Rev. Hematol., 2017, Vol. 10, no. 8, pp. 745-752.

26. Ma Y.Y., Zhao M., Liu Y. et al. Use of decitabine for patients with refractory or relapsed acute myeloid leukemia: a systematic review and meta-analysis. Hematology, 2019, Vol. 24, no. 1, pp. 507-515.

27. Montalban-Bravo G., Garcia-Manero G. Myelodysplastic syndromes: 2018 update on diagnosis, riskstratification and management. Am. J. Hematol., 2018,, Vol. 93, no. 1, pp. 129-147.

28. Muntasell A., Ochoa M.C., Cordeiro L. et al. Targeting NK-cell checkpoints for cancer immunotherapy. Curr. Opin. Immunol., 2017, Vol. 45 pp. 73-81.

29. Raneros A.B., Minguela A., Rodriguez R.M., Colado E., Bernal T., Anguita E., Mogorron A.V., Gil A.C., Vidal-Castiñeira J.R., Márquez-Kisinousky L., Bulnes P.D., Marin A.M., Garay M.C.G., Suarez-Alvarez B., LopezLarrea C. Increasing TIMP3 expression by hypomethylating agents diminishes soluble MICA, MICB and ULBP2 shedding in acute myeloid leukemia, facilitating NK cell-mediated immune recognition. Oncotarget, 2017, Vol. 8, no. 19, pp. 31959-31976.

30. Rohner A., Langenkamp U., Siegler U., Kalberer C.P., Wodnar-Filipowicz A. Differentiation-promoting drugs up-regulate NKG2D ligand expression and enhance the susceptibility of acute myeloid leukemia cells to natural killer cell-mediated lysis. Leuk. Res., 2007, Vol. 31, no. 10, pp. 1393-1402.

31. Sato T., Issa J.J., Kropf P. DNA hypomethylating drugs in cancer therapy. Cold Spring Harb. Perspect. Med., 2017, Vol. 7, no. 5, a026948. doi: 10.1101/cshperspect.a026948.

32. Schmiedel B.J., Arelin V., Gruenebach F., Krusch M., Schmidt S.M., Salih H.R. Azacytidine impairs NK cell reactivity while decitabine augments NK cell responsiveness toward stimulation. Int. J. Cancer, 2011, Vol. 128, no. 12, pp. 2911-2922.

33. Seelan R.S., Mukhopadhyay P., Pisano M.M., Greene R.M. Effects of 5-Aza-2’-deoxycytidine (decitabine) on gene expression. Drug Metab. Rev., 2018, Vol. 50, no. 2, pp. 193-207.

34. Sohlberg E., Pfefferle A., Andersson S., Baumann B.C., Hellstrom-Lindberg E., Malmberg K.J. Imprint of 5-azacytidine on the natural killer cell repertoire during systemic treatment for high-risk myelodysplastic syndrome. Oncotarget, 2015, Vol. 6, no. 33, pp. 34178-34190.

35. Strauss-Albee D.M., Fukuyama J., Liang E.C. et al. Human NK cell repertoire diversity reflects immune experience and correlates with viral susceptibility. Sci. Transl. Med., 2015, Vol. 7, 297, 297ra115. doi: 10.1126/scitranslmed.aac5722.

36. Vasu S., He S., Cheney C. Decitabine enhances anti-CD33 monoclonal antibody BI 836858-mediated natural killer ADCC against AML blasts. Blood, 2016, Vol. 127, no. 23, pp. 2879-2889.

37. Verheyden S., Bernier M., Demanet C. Identification of natural killer cell receptor phenotypes associated with leukemia. Leukemia, 2004, Vol. 18, no. 12, pp. 2002-2007.

38. Verheyden S., Demanet C. Susceptibility to myeloid and lymphoid leukemia is mediated by distinct inhibitory KIR-HLA ligand interactions. Leukemia, 2006, Vol. 20, no. 8, pp. 1437-1438.

39. Wang E.S. Treating acute myeloid leukemia in older adults. Hematology. Am. Soc. Hematol. Educ. Program, 2014, Vol. 2014, no. 1, pp. 14-20.

40. Wiencke J.K., Butler R., Hsuang G. et al. The DNA methylation profile of activated human natural killer cells. Epigenetics, Vol. 11, no. 5, pp. 363-380.

41. Yang H., Bueso-Ramos C., DiNardo C., Estecio M.R., Davanlou M., Geng Q.R., Fang Z., Nguyen M., Pierce S., Wei Y., Parmar S., Cortes J., Kantarjian H., Garcia-Manero G. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia, 2014, Vol. 28, no. 6, pp. 1280-1288.

42. Yu G., Wu Y., Wang W., Xu J., Lv X., Cao X., Wan T. Low-dose decitabine enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by re-modulating the tumor microenvironment. Cell. Mol. Immunol., 2019, Vol. 16, no. 4, pp. 401-409.

43. Zunke F., Rose-John S. The shedding protease ADAM17: physiology and pathophysiology. Biochim. Biophys. Acta Mol. Cell. Res., 2017, Vol. 1864, no. 11, Pt B, pp. 2059-2070.