Abstract
Regional lymph nodes (LN)s represent important immunological barriers in spreading of malignant tumors. However, they are the most frequent early metastatic site in melanoma. Immunomodulatory agents including cytokines have been included in therapy of melanoma and have shown severe side effects and toxicity. In this sense, there is a growing need for bringing these agents to further in vitro testing that may enlighten aspects of their regional application. Therefore, the aim of this study was to investigate the effect of interleukin (IL)-2 and IL-15, the two cytokines with similar immune-enhancing effects, on the expression of activating NKG2D, inhibitory CD158a and CD158b receptors on CD8+ T, NKT-like and NK cell lymphocyte subsets from regional LNs of melanoma patients. In this study, we showed significant effects of IL-2 and IL-15 cytokine treatments on the expression of activating NKG2D and on inhibitory CD158a and CD158b receptors on lymphocytes, CD8+ T, NKT-like and NK cell lymphocyte subsets originating from regional LNs of melanoma patients. Furthermore, IL-2 and IL-15 by inducing the expression of NKG2D activating receptor on innate and on adaptive lymphocyte subsets and by augmenting NK cell antitumor cytotoxicity that correlated with the cytokine-induced NKG2D expression, increased antitumor potential of immune cells in regional LNs of melanoma patients irrespective of LN involvement. These findings indicate the importance of immune cell population from regional LNs of melanoma patients in the development of immune intervention strategies that may if applied locally increase antitumor potential to the level that controls tumor progressions.
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References
Umansky V, Sevko A (2012) Melanoma-induced immunosuppression and its neutralization. Semin Cancer Biol 22:319–326
Grotz TE, Mansfield AS, Jakub JW, Markovic SN (2012) Regional lymphatic immunity in melanoma. Melanoma Res 22:9–18
Zheng R, Kjaergaard J, Lee WT, Cohen PA, Shu S (2007) Significance of regional draining lymph nodes in the development of tumor immunity: implications for cancer immunotherapy. Cancer Treat Res 135:223–237
Pulliam SR, Uzhachenko RV, Adunyah SE, Shanker A (2016) Common gamma chain cytokines in combinatorial immune strategies against cancer. Immunol Lett 169:61–72
Fewkes NM, Mackall CL (2010) Novel gamma-chain cytokines as candidate immune modulators in immune therapies for cancer. Cancer J 16:392–398
Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM, Ugolini S (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331:44–49
Zafirova B, Wensveen FM, Gulin M, Polić B (2011) Regulation of immune cell function and differentiation by the NKG2D receptor. Cell Mol Life Sci 68:3519–3529
Snyder MR, Weyand CM, Goronzy JJ (2004) The double life of NK receptors: stimulation or co-stimulation? Trends Immunol 25:25–32
Vivier E, Anfossi N (2004) Inhibitory NK-cell receptors on T cells: witness of the past, actors of the future. Nat Rev Immunol 4:190–198
Patterson S, Chaidos A, Neville DC, Poggi A, Butters TD, Roberts IA, Karadimitris A (2008) Human invariant NKT cells display alloreactivity instructed by invariant TCR-CD1d interaction and killer Ig receptors. J Immunol 181:3268–3276
Jackson A, Warner N (1986) Preparation, staining and analysis by flow cytometry of peripheral blood leukocytes. In: Rose N, Friedman H, Fahey J (eds) Manual of Clin Lab immunology, 3rd edn. American Society for Microbiology, Washington, pp 226–235
Vuletić AM, Jovanić IP, Jurišić VB, Milovanović ZM, Nikolić SS, Tanić NT, Konjević GM (2015) In-vitro activation of natural killer cells from regional lymph nodes of melanoma patients with interleukin-2 and interleukin-15. Melanoma Res 25:22–34
Cochran AJ, Huang RR, Lee J, Itakura E, Leong SP, Essner R (2006) Tumour-induced immune modulation of sentinel lymph nodes. Nat Rev Immunol 6:659–670
Farzad Z, Cochran AJ, McBrideWH GJD, Wong V, Morton L (1990) Lymphocyte subset alterations in nodes regional to human melanoma. Cancer Res 50:3585–35888
Vuletić A, Jovanić I, Jurišić V, Milovanović Z, Nikolić S, Spurnić I, Konjević G (2015) Decreased interferon γ production in CD3+ and CD3- CD56+ lymphocyte subsets in metastatic regional lymph nodes of melanoma patients. Pathol Oncol Res 21:1109–1114
Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, Urist M, McMasters KM, Ross MI, Kirkwood JM, Atkins MB, Thompson JA, Coit DG, Byrd D, Desmond R, Zhang Y, Liu PY, Lyman GH, Morabito A (2001) Prognostic factors analysis of 17,600 melanoma patients: validation of the American joint committee on Cancer melanoma staging system. J Clin Oncol 19:3622–3634
Vuletić A, Jurišić V, Jovanić I, Milovanović Z, Nikolić S, Konjević G (2013) Distribution of several activating and inhibitory receptors on CD3(−)CD56(+) NK cells in regional lymph nodes of melanoma patients. J Surg Res 183:860–868
Konjević G, Mirjacić Martinović K, Vuletić A, Jurisić V, Spuzić I (2009) Distribution of several activating and inhibitory receptors on CD3-CD16+ NK cells and their correlation with NK cell function in healthy individuals. J Membr Biol 230:113–123
Ali TH, Pisanti S, Ciaglia E, Mortarini R, Anichini A, Garofalo C, Tallerico R, Santinami M, Gulletta E, Ietto C, Galgani M, Matarese G, Bifulco M, Ferrone S, Colucci F, Moretta A, Kärre K, Carbone E (2014) Enrichment of CD56(dim)KIR + CD57 + highly cytotoxic NK cells in tumour-infiltrated lymph nodes of melanoma patients. Nat Commun 5:5639. https://doi.org/10.1038/ncomms6639
Keskin DB, Allan DS, Rybalov B, Andzelm MM, Stern JN, Kopcow HD, Koopman LA, Strominger JL (2007) TGFbeta promotes conversion of CD16+ peripheral blood NK cells into CD16- NK cells with similarities to decidual NK cells. Proc Natl Acad Sci U S A 104:3378–3383
Fransen MF, Arens R, Melief CJ (2013) Local targets for immune therapy to cancer: tumor draining lymph nodes and tumor microenvironment. Int J Cancer 132:1971–1976
Konjević G, Vuletić A, Mirjačić Martinović K (2016) Natural killer cell receptors: alterations and therapeutic targeting in malignancies. Immunol Res 64:25–35
Zhang C, Zhang J, Niu J, Zhang J, Tian Z (2008) Interleukin-15 improves cytotoxicity of natural killer cells via up-regulating NKG2D and cytotoxic effector molecule expression as well as STAT1 and ERK1/2 phosphorylation. Cytokine 42:128–136
Verhoeven DH, de Hooge AS, Mooiman EC, Santos SJ, ten Dam MM, Gelderblom H, Melief CJ, Hogendoorn PC, Egeler RM, van Tol MJ, Schilham MW, Lankester AC (2008) NK cells recognize and lyse Ewing sarcoma cells through NKG2D and DNAM-1 receptor dependent pathways. Mol Immunol 45:3917–3925
Hromadnikova I, Li S, Kotlabova K, Dickinson AM (2016) Influence of in vitro IL-2 or IL-15 alone or in combination with Hsp 70 derived 14-Mer peptide (TKD) on the expression of NK cell Activatory and inhibitory receptors on peripheral blood T cells, B cells and NKT cells. PLoS One 11:e0151535
Correia MP, Costa AV, Uhrberg M, Cardoso EM, Arosa FA (2011) IL-15 induces CD8+ T cells to acquire functional NK receptors capable of modulating cytotoxicity and cytokine secretion. Immunobiology 216:604–612
Decot V, Voillard L, Latger-Cannard V, Aissi-Rothé L, Perrier P, Stoltz JF, Bensoussan D (2010) Natural-killer cell amplification for adoptive leukemia relapse immunotherapy: comparison of three cytokines, IL-2, IL-15, or IL-7 and impact on NKG2D, KIR2DL1, and KIR2DL2 expression. Exp Hematol 38:351–362
Romagnani C, Juelke K, Falco M, Morandi B, D'Agostino A, Costa R, Ratto G, Forte G, Carrega P, Lui G, Conte R, Strowig T, Moretta A, Münz C, Thiel A, Moretta L, Ferlazzo G (2007) CD56brightCD16- killer Ig-like receptor- NK cells display longer telomeres and acquire features of CD56dim NK cells upon activation. J Immunol 178:4947–4955
Ferlazzo G, Thomas D, Lin SL, Goodman K, Morandi B, Muller WA, Moretta A, Münz C (2004) The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic. J Immunol 172:1455–1462
Cichocki F, Hanson RJ, Lenvik T, Pitt M, McCullar V, Li H, Anderson SK, Miller JS (2009) The transcription factor c-Myc enhances KIR gene transcription through direct binding to an upstream distal promoter element. Blood 113:3245–3253
Juelke K, Killig M, Thiel A, Dong J, Romagnani C (2009) Education of hyporesponsive NK cells by cytokines. Eur J Immunol 39:2548–2555
Konjevic G, Jurisic V, Jovic V, Vuletic A, Mirjacic Martinovic K, Radenkovic S, Spužić I (2012) Investigation of NK cell function and their modulation in different malignancies. Immunol Res 52:139–156
Konjević G, Mirjacić Martinović K, Vuletić A, Jović V, Jurisić V, Babović N, Spuzić I (2007) Low expression of CD161 and NKG2D activating NK receptor is associated with impaired NK cell cytotoxicity in metastatic melanoma patients. Clin Exp Metastasis 24:1–11
Seidel MG, Freissmuth M, Pehamberger H, Micksche M (1998) Stimulation of natural killer activity in peripheral blood lymphocytes of healthy donors and melanoma patients in vitro: synergism between interleukin (IL)-12 and IL-15 or IL-12 and IL-2. Naunyn Schmiedeberg's Arch Pharmacol 358:382–389
Sabry M, Lowdell MW (2013) Tumor-primed NK cells: waiting for the green light. Front Immunol 4:408
Konjević G, Mirjačić Martinović K, Vuletić A, Babović N (2010) In-vitro IL-2 or IFN-α- induced NKG2D and CD161 NK cell receptor expression indicates novel aspects of NK cell activation in metastatic melanoma patients. Melanoma Res 20:459–467
Topham NJ, Hewitt EW (2009) Natural killer cell cytotoxicity: how do they pull the trigger? Immunology 128:7–15
Guia S, Jaeger BN, Piatek S, Mailfert S, Trombik T, Fenis A, Chevrier N, Walzer T, Kerdiles YM, Marguet D, Vivier E, Ugolini S (2011) Confinement of activating receptors at the plasma membrane controls natural killer cell tolerance. Sci Signal 4:ra21
Acknowledgments
This study was supported by the grants of the Ministry of education, science and technological development of the Republic of Serbia: grant number 41031 and grant number 175056. The authors wish to thank Jasna Popovic Basić for excellent technical assistance and help during this research.
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Vuletić, A., Jovanić, I., Jurišić, V. et al. IL-2 And IL-15 Induced NKG2D, CD158a and CD158b Expression on T, NKT- like and NK Cell Lymphocyte Subsets from Regional Lymph Nodes of Melanoma Patients. Pathol. Oncol. Res. 26, 223–231 (2020). https://doi.org/10.1007/s12253-018-0444-2
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DOI: https://doi.org/10.1007/s12253-018-0444-2