Increased Perforin- and IL-21-Expressing NK Cells in Patients with Early-Stage Chronic Lymphocytic Leukemia

Year 2022, Volume: 12 Issue: 3, 225 - 231, 31.12.2022

Fatih Akboğa , Fehmi Hindilerden , Emine Gulturk , İpek Yönal Hindilerden , Abdullah Yılmaz , Gunnur Deniz , Metin Yusuf Gelmez

https://doi.org/10.26650/experimed.1191622

Abstract

Objective: CD5+CD19+ cells have a low proliferation capacity and elevated expression of anti-apoptotic protein BCL-2, mostly in the G0/G1 cell phase and accumulate in the pathogenesis of chronic lymphocytic leukemia(CLL). Natural killer (NK) cells have the ability to kill the intracellular pathogen-infected or cancer cells and secrete cytotoxic enzymes. This study evaluated the frequency, expression of cytotoxic enzymes, and intracellular cytokine levels of NK cells in CLL patients.

Materials and Methods: In this study, peripheral blood mononuclear cells were isolated from peripheral blood samples of CLL patients (n=29) and healthy controls (n=16) by density gradient centrifugation method.The frequency of the total NK cells and the intracellular levels of perforin, granzyme, interferon (IFN)-γ, interleukin (IL)-21, IL-4 and IL-17 in NK cells were investigated.

Results: Elevatedtotal NK cell frequency were found in the CLL patients compared to the healthy controls, and negatively correlated with CD5+CD19+ malign B cell frequency. Increased perforin expression was observed in patients’ total NK cells. Additionally, increased levels of IL-17 and IL-21 in total NK cell of CLL patients were obtained compared to healthy subjects.

Conclusion: The findings suggest that in the early stage of CLL, increased total NK cell frequency, and elevated perforin and IL-21 levels in NK cells might have a protective impact against the progression of the disease for CLL patients.

Keywords

Chronic Lymphocytic Leukemia, CLL, Natural Killer Cells, NK

Supporting Institution

This study was funded by Istanbul University

Project Number

project number TYL-2022-38452

References

• 1. Yosifov DY, Wolf C, Stilgenbauer S, Mertens D. From Biology to Therapy: The CLL Success Story. Hemasphere 2019; 3(2): e175. [CrossRef] google scholar
• 2. Rai KR, Jain P. Chronic lymphocytic leukemia (CLL)-Then and now. Am J Hematol 2016; 91(3): 330-40. [CrossRef] google scholar
• 3. Kay NE, Hampel PJ, Van Dyke DL, Parikh SA. CLL update 2022: A continuing evolution in care. Blood Rev 2022; 54: 100930. [CrossRef] google scholar
• 4. Hallek M. Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment. Am J Hematol 2019; 94(11): 1266-87. [CrossRef] google scholar
• 5. Malavasi F, Deaglio S, Damle R, Cutrona G, Ferrarini M, Chiorazzi N. CD38 and chronic lymphocytic leukemia: a decade later. Blood 2011; 118(13): 3470-8. [CrossRef] google scholar
• 6. Kucuksezer UC, Aktas Cetin E, Esen F, Tahrali I, Akdeniz N, Gelmez MY, et al. The Role of natural killer cells in autoimmune diseases. Front Immunol 2021; 12: 622306. [CrossRef] google scholar
• 7. Gardiner CM. NK cell metabolism. J Leukoc Biol 2019; 105(6): 1235-42. [CrossRef] google scholar
• 8. Bi J, Tian Z. NK cell dysfunction and checkpoint immunotherapy. Front Immunol 2019; 10: 1999. [CrossRef] google scholar
• 9. Sportoletti P, De Falco F, Del Papa B, Baldoni S, Guarente V, Marra A, et al. NK cells in chronic lymphocytic leukemia and their therapeutic implications. Int J Mol Sci 2021; 22(13). [CrossRef] google scholar
• 10. Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res 2015; 21(4): 687-92. [CrossRef] google scholar
• 11. Yao Y, Lin X, Li F, Jin J, Wang H. The global burden and attributable risk factors of chronic lymphocytic leukemia in 204 countries and territories from 1990 to 2019: analysis based on the global burden of disease study 2019. Biomed Eng Online 2022; 21(1): 4. [CrossRef] google scholar
• 12. Yoshino T, Tanaka T, Sato Y. Differential diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma and other indolent lymphomas, including mantle cell lymphoma. J Clin Exp Hematop 2020; 60(4): 124-9. [CrossRef] google scholar
• 13. Chennamadhavuni A, Lyengar V, Shimanovsky A. Leukemia. In StatPearls. Treasure Island (FL); 2022. google scholar
• 14. Vlachonikola E, Stamatopoulos K, Chatzidimitriou A. T cells in chronic lymphocytic leukemia: A two-edged sword. Front Immunol 2020; 11: 612244. [CrossRef] google scholar
• 15. MacFarlane AWt, Jillab M, Smith MR, Alpaugh RK, Cole ME, Litwin S, et al. NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors. Oncoimmunology 2017; 6(7): e1330235. [CrossRef] google scholar
• 16. Zhu F, McCaw L, Spaner DE, Gorczynski RM. Targeting the IL-17/ IL-6 axis can alter growth of chronic lymphocytic leukemia in vivo/ in vitro. Leuk Res 2018; 66: 28-38. [CrossRef] google scholar
• 17. Zhao J, Chen X, Herjan T, Li X. The role of interleukin-17 in tumor development and progression. J Exp Med 2020; 217(1). [CrossRef] google scholar
• 18. Chen J, Liao MY, Gao XL, Zhong Q, Tang TT, Yu X, et al. IL-17A induces pro-inflammatory cytokines production in macrophages via MAPKinases, NF-KappaB and AP-1. Cell Physiol Biochem 2013; 32(5): 1265-74. [CrossRef] google scholar
• 19. Bankir M, Acik DY. IL-17 and IL-23 levels in patients with early-stage chronic lymphocytic leukemia. North Clin Istanb 2021; 8(1): 24-30. [CrossRef] google scholar
• 20. Jain P, Javdan M, Feger FK, Chiu PY, Sison C, Damle RN, et al. Th17 and non-Th17 interleukin-17-expressing cells in chronic lymphocytic leukemia: delineation, distribution, and clinical relevance. Haematologica 2012; 97(4): 599-607. [CrossRef] google scholar
• 21. Martinez-Espinosa I, Serrato JA, Ortiz-Quintero B. Role of IL-10-producing natural killer cells in the regulatory mechanisms of inflammation during systemic infection. Biomolecules 2021; 12(1). [CrossRef] google scholar
• 22. Phoksawat W, Jumnainsong A, Leelayuwat N, Leelayuwat C. IL-17 production by NKG2D-expressing CD56+ T cells in type 2 diabetes. Mol Immunol 2019; 106: 22-8. [CrossRef] google scholar
• 23. Fayad L, Keating MJ, Reuben JM, O'Brien S, Lee BN, Lerner S, et al. Interleukin-6 and interleukin-10 levels in chronic lymphocytic leukemia: correlation with phenotypic characteristics and outcome. Blood 2001; 97(1): 256-63. [CrossRef] google scholar
• 24. De Cecco L, Capaia M, Zupo S, Cutrona G, Matis S, Brizzolara A, et al. Interleukin 21 Controls mRNA and MicroRNA expression in CD40-activated chronic lymphocytic leukemia cells. PLoS One 2015; 10(8): e0134706. [CrossRef] google scholar
• 25. de Totero D, Meazza R, Capaia M, Fabbi M, Azzarone B, Balleari E, et al. The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways. Blood 2008; 111(2): 517-24. [CrossRef] google scholar
• 26. Brady J, Hayakawa Y, Smyth MJ, Nutt SL. IL-21 induces the functional maturation of murine NK cells. J Immunol 2004; 172(4): 2048-58. [CrossRef] google scholar