Original Article
  

SDF-1α Reduces Human Natural Killer Cell Cytotoxicity against Chronic Myelogenous Leukemia K562 Cells

Abstract

Stromal cell-derived factor-1 alpha (SDF-1α) has been shown to be up-regulated in a variety of malignancies. So that, its expression is associated with poor prognosis and invasiveness. Natural killer (NK) cells are important effector cells against virus-infected and transformed cells. Especially they play a key role in tumor immune surveillance. Whereas it was not well understood whether SDF-1α modulates anti-tumor immune response or not, the purpose of the present study was to investigate the effect of SDF-1α on the cytotoxic properties of peripheral blood NK cells. Human peripheral blood NK cells were freshly isolated using MACSxpess system and cultured in the presence or absence of recombinant human SDF-1α or SDF-1α plus CXCR4 antagonist, AMD3100. CD107a degranulation assay was conducted through the co-culture of NK cells with K562 cells. The percentage of CD107a positive cells was assessed by flowcytometry. Effect of SDF-1α was also examined on the mRNA levels of NKG2A and NKG2D as indicator examples of NK cell inhibitory and activating receptors, respectively. SDF-1α significantly decreased the degranulation activity of NK cells (p=0.04). The mRNA content of NKG2D was down-regulated under the influence of SDF-1α (p=0.03). Moreover, AMD3100 exhibited a trend in recovering the NKG2D mRNA level to its un-treated state (p=0.05).  The present study reveals that SDF-1α has a negative impact on NK cell activity and might is involved in tumor immune-suppression. Thus, it can be concluded that microenvironment manipulations targeting SDF-1α may reinforce current cancer therapies by disturbing one of the immune-suppressive axes in the cancerous milieu. 

1. Dehne N, Mora J, Namgaladze D, Weigert A, Brüne B. Cancer cell and macrophage cross-talk in the tumor microenvironment. Curr Opin Pharmacol 2017; 35:12–9.
2. Burkholder B, Huang R-Y, Burgess R, Luo S, Jones VS, Zhang W, et al. Tumor-induced perturbations of cytokines and immune cell networks. Biochim Biophys Acta 2014; 1845(2):182–201.
3. Shirozu M, Nakano T, Inazawa J, Tashiro K, Tada H, Shinohara T, et al. Structure and chromosomal localization of the human stromal cell-derived factor 1 (SDF1) gene. Genomics 1995; 28(3):495–500.
4. Abbas AK, Lichtman AHH, Pillai S. Cellular and Molecular Immunology: with STUDENT CONSULT Online Access. Elsevier Health Sciences; 2014.
5. Sterlacci W, Saker S, Huber B, Fiegl M, Tzankov A. Expression of the CXCR4 ligand SDF-1/CXCL12 is prognostically important for adenocarcinoma and large cell carcinoma of the lung. Virchows Arch 2016; 468(4):463–71.
6. Samarendra H, Jones K, Petrinic T, Silva MA, Reddy S, Soonawalla Z, et al. A meta-analysis of CXCL12 expression for cancer prognosis. Br J Cancer 2017; 117(1):124-35.
7. Song Z, Zhang X, Ye X, Feng C, Yang G, Lu Y, et al. High Expression of Stromal Cell-Derived Factor 1 (SDF-1) and NF-$κ$B Predicts Poor Prognosis in Cervical Cancer. Med Sci Monit Int Med J Exp Clin Res 2017; 23:151-57.
8. Sun X, Cheng G, Hao M, Zheng J, Zhou X, Zhang J, et al. CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev 2010; 29(4):709–22.
9. Gil M, Komorowski MP, Seshadri M, Rokita H, McGray AJR, Opyrchal M, et al. CXCL12/CXCR4 blockade by oncolytic virotherapy inhibits ovarian cancer growth by decreasing immunosuppression and targeting cancer-initiating cells. J Immunol. Am Assoc Immnol 2014; 193(10):5327–37.
10. Feig C, Jones JO, Kraman M, Wells RJB, Deonarine A, Chan DS, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti--PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci 2013; 110(50):20212–7.
11. Vitiello L, Ferraro E, De Simone S, Gatta L, Feraco A, Racioppi L, et al. CXCL12 prolongs naive CD4+ T lymphocytes survival via activation of PKA, CREB and Bcl2 and BclXl up-regulation. Int J Cardiol 2016; 224:206–12.
12. Noda M, Omatsu Y, Sugiyama T, Oishi S, Fujii N, Nagasawa T. CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adult mice. Blood 2011; 117(2):451–8.
13. Xing R, Li L, Chen L, Gao Z, Wang H, Li W, et al. Copy number variations of HLA-I and activation of NKp30 pathway determine the sensitivity of gastric cancer cells to the cytotoxicity of natural killer cells. Oncogene 2016; 35(20):2584-91:
14. Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 2008; 9(5):495-502.
15. Meyer CE, Key PN, Zhu T, Shabsovich M, Ni A, Tripathy SK. Expression of the inhibitory receptor NKG2A correlates with increased liver and splenic NK cell response to activating receptor engagement. Immun Inflamm Dis 2017; 5(2):177–89.
16. Martin-Antonio B, Najjar A, Robinson SN, Chew C, Li S, Yvon E, et al. Transmissible cytotoxicity of multiple myeloma cells by cord blood-derived NK cells is mediated by vesicle trafficking. Cell Death Differ 2015; 22(1):96–107.
17. Dürr C, Pfeifer D, Claus R, Schmitt-Graeff A, Gerlach U V, Graeser R, et al. CXCL12 mediates immunosuppression in the lymphoma microenvironment after allogeneic transplantation of hematopoietic cells. Cancer Res 2010; 70(24):10170–81.
18. Bodnar RJ. Chemokine regulation of angiogenesis during wound healing. Adv wound care. Mary Ann Liebert, Inc. 140 Huguenot Street, 3rd Floor New Rochelle, NY 10801 USA 2015; 4(11):641–50.
19. Cheng JW, Sadeghi Z, Levine AD, Penn MS, von Recum HA, Caplan AI, et al. The role of CXCL12 and CCL7 chemokines in immune regulation, embryonic development, and tissue regeneration. Cytokine 2014; 69(2):277–83.
20. Busillo JM, Benovic JL. Regulation of CXCR4 signaling. Biochim Biophys Acta 2007; 1768(4):952–63.
21. Kowalski K, Kołodziejczyk A, Sikorska M, Płaczkiewicz J, Cichosz P, Kowalewska M, et al. Stem cells migration during skeletal muscle regeneration-the role of Sdf-1/Cxcr4 and Sdf-1/Cxcr7 axis. Cell Adh Migr 2017; 11(4):384–98.
22. Wiesmayr S, Webber SA, Macedo C, Popescu I, Smith L, Luce J, et al. Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD. Eur J Immunol 2012; 42(2):541–50.
Files
IssueVol 18, No 5 (2019) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijaai.v18i5.1917
PMID32245293
Keywords
Immunologic cytotoxicity Killer cells Natural NKG2D SDF-1α
Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Mardomi A, Hossein-Nataj H, Jafari N, Mohammadi N, Abediankenari S. SDF-1α Reduces Human Natural Killer Cell Cytotoxicity against Chronic Myelogenous Leukemia K562 Cells. Iran J Allergy Asthma Immunol. 2019;18(5):493-500.