Abstract
We recently reported that pretreatment of IL-2 activated human natural killer (NK) cells with the drugs dimethyl fumarate (DMF) and monomethyl fumarate (MMF) upregulated the expression of surface chemokine receptor CCR10. Ligands for CCR10, namely CCL27 and CCL28, induced the chemotaxis of these cells. Here, we performed a bioinformatics analysis to see which chemokines might be expressed by the human HCT-116 colorectal cancer cells. We observed that, in addition to CCL27 and CCL28, HCT-116 colorectal cancer cells profoundly express CXCL16 which binds CXCR6. Consequently, NK92 cells were treated with DMF and MMF for 24 h to investigate in vitro chemotaxis towards CXCL16, CCL27, and CCL28. Furthermore, supernatants collected from HCT-116 cells after 24 or 48 h incubation induced the chemotaxis of NK92 cells. Similar to their effects on human IL-2-activated NK cells, MMF and DMF enhanced the expression of CCR10 and CXCR6 in NK92 cells. Neutralizing anti-CXCL16 or anti-CCL28 inhibited the chemotactic effects of 24 and 48 supernatants, whereas anti-CCL27 only inhibited the 48 h supernatant activity, suggesting that 24 h supernatant contains CXCL16 and CCL28, whereas HCT-116 secretes all three chemokines after 48 h in vitro cultures. CXCL16, CCL27, and CCL28, as well as the supernatants collected from HCT-116, induced the mobilization of (Ca)2+ in NK92 cells. Cross-desensitization experiments confirmed the results of the chemotaxis experiments. Finally, incubation of NK92 cells with HCT-116 induced the lysis of the tumor cells. In summary, these results might have important implications in directing the anti-tumor effectors NK cells towards tumor growth sites.
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Abbreviations
- CCL/CCR:
-
CC chemokine ligand/chemokine receptor
- CTACK:
-
Cutaneous T-cell-attracting chemokine/CCL27
- CXCL/CXCR:
-
CXC chemokine ligand/chemokine receptor
- DMF:
-
Dimethyl fumarate
- DMSO:
-
Dimethyl sulfoxide
- DNA:
-
Deoxyribonucleic acid
- EAE:
-
Experimental autoimmune encephalomyelitis
- EGTA:
-
Ethylene glycol-bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
- ELISA:
-
Enzyme-linked immunosorbent assay
- FU:
-
Fluorescence units
- HRP:
-
Horseradish peroxidase
- MI:
-
Migration index
- MMF:
-
Monomethyl fumarate
- mRNA:
-
Messenger RNA
- MS:
-
Multiple sclerosis
- NK:
-
Natural killer
- PDL-1:
-
Program death ligand-1
- qRT-PCR:
-
Real-time quantitative polymerase chain reaction
- RNA:
-
Ribonucleic acid
- RPMI:
-
Roswell Park Memorial Institute
- Treg:
-
Regulatory T cells
References
Pampena MB, Levy EM (2015) Natural killer cells as helper cells in dendritic cell cancer vaccines. Front Immunol 6:13. https://doi.org/10.3389/fimmu.2015.00013
Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22(11):633–640. https://doi.org/10.1016/S1471-4906(01)02060-9
Maghazachi AA (2005) Compartmentalization of human natural killer cells. Mol Immunol 42(4):523–529. https://doi.org/10.1016/j.molimm.2004.07.036
Maghazachi AA (2010) Role of chemokines in the biology of natural killer cells. Curr Top Microbiol Immunol 341:37–58. https://doi.org/10.1007/82_2010_20
Rocca YS, Roberti MP, Juliá EP, Pampena MB, Bruno L, Rivero S, Huertas E, Sánchez Loria F, Pairola A, Caignard A, Mordoh J, Levy EM (2016) Phenotypic and functional dysregulated blood NK cells in colorectal cancer patients can be activated by cetuximab plus IL-2 or IL-15. Front Immunol 7:413. https://doi.org/10.3389/fimmu.2016.00413
Schlöder J, Berges C, Luessi F, Jonuleit H (2017) Dimethyl fumarate therapy significantly improves the responsiveness of T cells in multiple sclerosis patients for immunoregulation by regulatory T Cells. Int J Mol Sci 18(2):271. https://doi.org/10.3390/ijms18020271
Selman M, Ou P, Rousso C, Bergeron A, Krishnan R, Pikor L, Chen A, Keller BA, Ilkow C, Bell JC, Diallo J-S (2018) Dimethyl fumarate potentiates oncolytic virotherapy through NF-κB inhibition. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aao1613
Al-Jaderi Z, Maghazachi AA (2016) Utilization of dimethyl fumarate and related molecules for treatment of multiple sclerosis, cancer, and other diseases. Front Immunol 7:278
Loewe R, Valero T, Kremling S, Pratscher B, Kunstfeld R, Pehamberger H, Petzelbauer P (2006) Dimethyl fumarate impairs melanoma growth and metastasis. Cancer Res 66(24):11888–11896. https://doi.org/10.1158/0008-5472.CAN-06-2397
Linker RA, Haghikia A (2016) Dimethyl fumarate in multiple sclerosis: latest developments, evidence and place in therapy. Ther Adv Chronic Dis 7(4):198–207. https://doi.org/10.1177/2040622316653307
Brennan MS, Patel H, Allaire N, Thai A, Cullen P, Ryan S, Lukashev M, Bista P, Huang R, Rhodes KJ, Scannevin RH (2016) Pharmacodynamics of dimethyl fumarate are tissue specific and involve NRF2-dependent and -independent mechanisms. Antioxid Redox Signal 24(18):1058–1071. https://doi.org/10.1089/ars.2015.6622
Al-Jaderi Z, Maghazachi AA (2015) Vitamin D3 and monomethyl fumarate enhance natural killer cell lysis of dendritic cells and ameliorate the clinical score in mice suffering from experimental autoimmune encephalomyelitis. Toxins 7(11):4730–4744. https://doi.org/10.3390/toxins7114730
Vego H, Sand KL, Høglund RA, Fallang L-E, Gundersen G, Holmøy T, Maghazachi AA (2016) Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a. Cell Mol Immunol 13(1):57–64. https://doi.org/10.1038/cmi.2014.114
Maghazachi AA, Sand KL, Al-Jaderi Z (2016) Glatiramer acetate, dimethyl fumarate, and monomethyl fumarate upregulate the expression of CCR10 on the surface of natural killer cells and enhance their chemotaxis and cytotoxicity. Front Immunol 7:437. https://doi.org/10.3389/fimmu.2016.00437
Martinez-Rodriguez M, Thompson AK, Monteagudo C (2017) High CCL27 immunoreactivity in ‘supratumoral’ epidermis correlates with better prognosis in patients with cutaneous malignant melanoma. J Clin Pathol 70(1):15. https://doi.org/10.1136/jclinpath-2015-203537
Dimberg J, Hugander A, Wågsäter D (2006) Protein expression of the chemokine, CCL28, in human colorectal cancer. Int J Oncol 28(2):315–319
Klingemann H, Boissel L, Toneguzzo F (2016) Natural killer cells for immunotherapy—advantages of the NK-92 cell line over blood NK cells. Front Immunol 7:91. https://doi.org/10.3389/fimmu.2016.00091
Diandong H, Kefeng S, Weixin F, Moran W, Jiahui W, Zaifu L (2014) The role of Gαs in activation of NK92-MI cells by neuropeptide substance P. Neuropeptides 48(1):1–5. https://doi.org/10.1016/j.npep.2013.12.001
Gdynia G, Sauer SW, Kopitz J, Fuchs D, Duglova K, Ruppert T, Miller M, Pahl J, Cerwenka A, Enders M, Mairbäurl H, Kamiński MM, Penzel R, Zhang C, Fuller JC, Wade RC, Benner A, Chang-Claude J, Brenner H, Hoffmeister M, Zentgraf H, Schirmacher P, Roth W (2016) The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration. Nat Commun 7:10764. https://doi.org/10.1038/ncomms10764
Jochems C, Hodge JW, Fantini M, Tsang KY, Vandeveer AJ, Gulley JL, Schlom J (2017) ADCC employing an NK cell line (haNK) expressing the high affinity CD16 allele with avelumab, an anti-PD-L1 antibody. Int J Cancer 141(3):583–593. https://doi.org/10.1002/ijc.30767
Rolin J, Sand KL, Knudsen E, Maghazachi AA (2010) FTY720 and SEW2871 reverse the inhibitory effect of S1P on natural killer cell mediated lysis of K562 tumor cells and dendritic cells but not on cytokine release. Cancer Immunol Immunother 59(4):575–586
Rouillard AD, Gundersen GW, Fernandez NF, Wang Z, Monteiro CD, McDermott MG, Ma’ayan A (2016) The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database (Oxford). https://doi.org/10.1093/database/baw100
Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, Wilson CJ, Lehár J, Kryukov GV, Sonkin D, Reddy A, Liu M, Murray L, Berger MF, Monahan JE, Morais P, Meltzer J, Korejwa A, Jané-Valbuena J, Mapa FA, Thibault J, Bric-Furlong E, Raman P, Shipway A, Engels IH, Cheng J, Yu GK, Yu J, Aspesi P, de Silva M, Jagtap K, Jones MD, Wang L, Hatton C, Palescandolo E, Gupta S, Mahan S, Sougnez C, Onofrio RC, Liefeld T, MacConaill L, Winckler W, Reich M, Li N, Mesirov JP, Gabriel SB, Getz G, Ardlie K, Chan V, Myer VE, Weber BL, Porter J, Warmuth M, Finan P, Harris JL, Meyerson M, Golub TR, Morrissey MP, Sellers WR, Schlegel R, Garraway LA (2012) The cancer cell line encyclopedia enables predictive modeling of anticancer drug sensitivity. Nature 483(7391):603–607. https://doi.org/10.1038/nature11003
Berahovich RD, Lai NL, Wei Z, Lanier LL, Schall TJ (2006) Evidence for NK cell subsets based on chemokine receptor expression. J Immunol 177(11):7833. https://doi.org/10.4049/jimmunol.177.11.7833
Maghazachi AA (2000) Intracellular signaling events at the leading edge of migrating cells. Int J Biochem Cell Biol 32(9):931–943. https://doi.org/10.1016/S1357-2725(00)00035-2
Wang L, Knudsen E, Jin Y, Gessani S, Maghazachi AA (2004) Lysophospholipids and chemokines activate distinct signal transduction pathways in T helper 1 and T helper 2 cells. Cell Signal 16(9):991–1000. https://doi.org/10.1016/j.cellsig.2004.02.001
Bressan A, Bigioni M, Bellarosa D, Nardelli F, Irrissuto C, Maggi CA, Binaschi M (2010) Induction of a less aggressive phenotype in human colon carcinoma HCT116 cells by chronic exposure to HDAC inhibitor SAHA. Oncol Rep 24(5):1249–1255
Lanuza PM, Vigueras A, Olivan S, Prats AC, Costas S, Llamazares G, Sanchez-Martinez D, Ayuso JM, Fernandez L, Ochoa I, Pardo J (2018) Activated human primary NK cells efficiently kill colorectal cancer cells in 3D spheroid cultures irrespectively of the level of PD-L1 expression. OncoImmunology 7(4):e1395123. https://doi.org/10.1080/2162402X.2017.1395123
Rajput A, Dominguez San Martin I, Rose R, Beko A, LeVea C, Sharratt E, Mazurchuk R, Hoffman RM, Brattain MG, Wang J (2008) Characterization of HCT116 human colon cancer cells in an orthotopic model. J Surg Res 147(2):276–281. https://doi.org/10.1016/j.jss.2007.04.021
Okada N, Sasaki A, Niwa M, Okada Y, Hatanaka Y, Tani Y, Mizuguchi H, Nakagawa S, Fujita T, Yamamoto A (2005) Tumor suppressive efficacy through augmentation of tumor-infiltrating immune cells by intratumoral injection of chemokine-expressing adenoviral vector. Cancer Gene Ther 13:393–405. https://doi.org/10.1038/sj.cgt.7700903
Okada N, Gao J-Q, Sasaki A, Niwa M, Okada Y, Nakayama T, Yoshie O, Mizuguchi H, Hayakawa T, Fujita T, Yamamoto A, Tsutsumi Y, Mayumi T, Nakagawa S (2004) Anti-tumor activity of chemokine is affected by both kinds of tumors and the activation state of the host’s immune system: implications for chemokine-based cancer immunotherapy. Biochem Biophys Res Commun 317(1):68–76. https://doi.org/10.1016/j.bbrc.2004.03.013
Pivarcsi A, Müller A, Hippe A, Rieker J, van Lierop A, Steinhoff M, Seeliger S, Kubitza R, Pippirs U, Meller S, Gerber PA, Liersch R, Buenemann E, Sonkoly E, Wiesner U, Hoffmann TK, Schneider L, Piekorz R, Enderlein E, Reifenberger J, Rohr U-P, Haas R, Boukamp P, Haase I, Nürnberg B, Ruzicka T, Zlotnik A, Homey B (2007) Tumor immune escape by the loss of homeostatic chemokine expression. Proc Natl Acad Sci USA 104(48):19055. https://doi.org/10.1073/pnas.0705673104
John AE, Thomas MS, Berlin AA, Lukacs NW (2005) Temporal production of CCL28 corresponds to eosinophil accumulation and airway hyperreactivity in allergic airway inflammation. Am J Pathol 166(2):345–353. https://doi.org/10.1016/S0002-9440(10)62258-4
Mohan T, Deng L, Wang B-Z (2017) CCL28 chemokine: an anchoring point bridging innate and adaptive immunity. Int Immunopharmacol 51:165–170. https://doi.org/10.1016/j.intimp.2017.08.012
Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, Gimotty PA, Gilks CB, Lal P, Zhang L, Coukos G (2011) Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475(7355):226–230. https://doi.org/10.1038/nature10169
Gao J-Q, Tsuda Y, Han M, Xu D-H, Kanagawa N, Hatanaka Y, Tani Y, Mizuguchi H, Tsutsumi Y, Mayumi T, Okada N, Nakagawa S (2008) NK cells are migrated and indispensable in the anti-tumor activity induced by CCL27 gene therapy. Cancer Immunol Immunother 58(2):291. https://doi.org/10.1007/s00262-008-0554-x
Liang H, Zhang Z, He L, Wang Y (2016) CXCL16 regulates cisplatin-induced acute kidney injury. Oncotarget 7(22):31652–31662. https://doi.org/10.18632/oncotarget.9386
Izquierdo MC, Martin-Cleary C, Fernandez-Fernandez B, Elewa U, Sanchez-Niño MD, Carrero JJ, Ortiz A (2014) CXCL16 in kidney and cardiovascular injury. Cytokine Growth Factor Rev 25(3):317–325. https://doi.org/10.1016/j.cytogfr.2014.04.002
Liang K, Liu Y, Eer D, Liu J, Yang F, Hu K (2018) High CXC chemokine ligand 16 (CXCL16) expression promotes proliferation and metastasis of lung cancer via regulating the NF-κB pathway. Med Sci Monit 24:405–411
Lang K, Bonberg N, Robens S, Behrens T, Hovanec J, Deix T, Braun K, Roghmann F, Noldus J, Harth V, Jockel KH, Erbel R, Tam YC, Tannapfel A, Kafferlein HU, Bruning T (2017) Soluble chemokine (C-X-C motif) ligand 16 (CXCL16) in urine as a novel biomarker candidate to identify high grade and muscle invasive urothelial carcinomas. Oncotarget 8(62):104946–104959. https://doi.org/10.18632/oncotarget.20737
Ke C, Ren Y, Lv L, Hu W, Zhou W (2017) Association between CXCL16/CXCR6 expression and the clinicopathological features of patients with non-small cell lung cancer. Oncol Lett 13(6):4661–4668. https://doi.org/10.3892/ol.2017.6088
Ajona D, Zandueta C, Corrales L, Moreno H, Pajares MJ, Ortiz-Espinosa S, Martinez-Terroba E, Perurena N, de Miguel FJ, Jantus-Lewintre E, Camps C, Vicent S, Agorreta J, Montuenga LM, Pio R, Lecanda F (2018) Blockade of the complement C5a/C5aR1 axis impairs lung cancer bone metastasis by CXCL16-mediated effects. Am J Respir Crit Care Med. https://doi.org/10.1164/rccm.201703-0660OC
Yoon MS, Pham CT, Phan MTT, Shin DJ, Jang YY, Park MH, Kim SK, Kim S, Cho D (2016) Irradiation of breast cancer cells enhances CXCL16 ligand expression and induces the migration of natural killer cells expressing the CXCR6 receptor. Cytotherapy 18(12):1532–1542. https://doi.org/10.1016/j.jcyt.2016.08.006
Hudspeth K, Donadon M, Cimino M, Pontarini E, Tentorio P, Preti M, Hong M, Bertoletti A, Bicciato S, Invernizzi P, Lugli E, Torzilli G, Gershwin ME, Mavilio D (2016) Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways. J Autoimmun 66:40–50. https://doi.org/10.1016/j.jaut.2015.08.011
Hojo S, Koizumi K, Tsuneyama K, Arita Y, Cui Z, Shinohara K, Minami T, Hashimoto I, Nakayama T, Sakurai H, Takano Y, Yoshie O, Tsukada K, Saiki I (2007) High-level expression of chemokine CXCL16 by tumor cells correlates with a good prognosis and increased tumor-infiltrating lymphocytes in colorectal cancer. Cancer Res 67(10):4725. https://doi.org/10.1158/0008-5472.CAN-06-3424
Rolin J, Maghazachi AA (2011) Effects of lysophospholipids on tumor microenvironment. Cancer Microenviron 4(3):393–403. https://doi.org/10.1007/s12307-011-0088-1
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This work was supported by the University of Sharjah Grants with numbers 1701090222-P and 1701090223-P.
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NME performed most of the experiments and wrote the paper; ZAJ performed the calcium assays; MYH performed the bioinformatics and qRT-PCR; AAM designed the experiments, performed the statistical analysis, and wrote the manuscript.
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The work described in this paper was performed using commercially available cell lines. This article does not contain any studies involving patients or experimental animals. Therefore, no study approval was required and no informed consent from the donors.
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The human natural killer cell line NK92 (CRL-2407), colorectal cancer cell line HCT-116 (CCL-247), and the erythroleukemia K562 (CCL-243) were obtained from the American type culture collection (ATCC, Manassas, VA, USA). No cell line authentication was necessary.
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Elemam, N.M., Al-Jaderi, Z., Hachim, M.Y. et al. HCT-116 colorectal cancer cells secrete chemokines which induce chemoattraction and intracellular calcium mobilization in NK92 cells. Cancer Immunol Immunother 68, 883–895 (2019). https://doi.org/10.1007/s00262-019-02319-7
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DOI: https://doi.org/10.1007/s00262-019-02319-7