Abstract
Tumor cells stimulate natural killer (NK) cell effector functions, but the regulation of cytokine secretion and cytolysis is incompletely understood. We tested whether oral and pharyngeal squamous cell carcinoma cell lines differentially stimulated NK cell interferon-γ (IFN-γ) secretion and cytolysis using a clone of the NK-92-transformed human NK cell line, NK92.35. SCC-4 and SCC-25 cells, but not FaDu or Cal 27 cells, stimulated robust NK92.35 IFN-γ secretion. All four carcinoma cell lines were lysed by NK92.35 cells. These findings indicate that carcinoma cells differentially stimulate NK cell IFN-γ secretion and cytolysis. In Transwell experiments, a combination of SCC-4 or SCC-25 cell soluble factors and contact with FaDu cells synergistically stimulated NK92.35 cell IFN-γ secretion. Stimulatory SCC-4 cells constitutively secreted IL-18, a cytokine that potently augments IFN-γ secretion by T cells and NK cells. In contrast, poorly stimulatory FaDu cells produced little or no IL-18, but synergized with recombinant IL-18 to stimulate NK92.35 IFN-γ secretion. mAb to IL-18 or IL-18 receptor diminished SCC-4-stimulated IFN-γ secretion by NK92.35 cells and by nontransformed NK cells. Thus, IL-18 was necessary for optimal carcinoma stimulation of NK cell IFN-γ secretion. In vivo, oral and upper aerodigestive tract epithelia and carcinomas produced IL-18, but one squamous cell carcinoma had heterogeneous IL-18 expression. Thus IL-18 production can account for squamous cell carcinoma differential stimulation of NK cell effector functions in vitro and may be important for stimulation of NK cells in vivo.
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Abbreviations
- A-NK:
-
IL-2-activated human NK cell
- IFN-γ:
-
Interferon-γ
- KIR:
-
Killer immunoglobulin-like receptor
- IL:
-
Interleukin
- mAb:
-
Monoclonal antibody
- MHC:
-
Major histocompatibility complex
- NK:
-
Natural killer
- TRAIL:
-
Tumor necrosis factor-related apoptosis-inducing ligand
References
Akira S (2000) The role of IL-18 in innate immunity. Curr Opin Immunol 12:59
Ballas ZK, Turner JM, Turner DA, Goetzman EA, Kemp JD (1990) A patient with simultaneous absence of "classical" natural killer cells (CD3−, CD16+, and NKH1+) and expansion of CD3+, CD4−, CD8−, NKH1+ subset. J Allergy Clin Immunol 85:453
Billiau A (1996) Interferon-gamma: biology and role in pathogenesis. Adv Immunol 62:61
Bohn E, Sing A, Zumbihl R, Bielfeldt C, Okamura H, Kurimoto M, Heesemann J, Autenrieth IB (1998) IL-18 (IFN-gamma-inducing factor) regulates early cytokine production in, and promotes resolution of, bacterial infection in mice. J Immunol 160:299
Chikamatsu K, Reichert TE, Kashii Y, Saito T, Kawashiri S, Yamamoto E, Whiteside TL (1999) Immunotherapy with effector cells and IL-2 of lymph node metastases of human squamous-cell carcinoma of the head and neck established in nude mice. Int J Cancer 82:532
Cho D, Song H, Kim YM, Houh D, Hur DY, Park H, Yoon D, Pyun KH, Lee WJ, Kurimoto M, Kim YB, Kim YS, Choi I (2000) Endogenous interleukin-18 modulates immune escape of murine melanoma cells by regulating the expression of Fas ligand and reactive oxygen intermediates. Cancer Res 60:2703
Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22:633
Dalbeth N, Callan MF (2002) A subset of natural killer cells is greatly expanded within inflamed joints. Arthritis Rheum 46:1763
Gong J-H, Maki G, Klingemann H-G (1994) Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia 8:652
Harriman GR (1991) Measurement of mouse and human interleukin 5. In: Coligan JE, Kruisbeek AM, Margulies DH, Shevach EM, Strober W (eds) Current protocols in immunology, vol 1. Wiley, New York, p 6.5.1
Hashimoto W, Osaki T, Okamura H, Robbins PD, Kurimoto M, Nagata S, Lotze MT, Tahara H (1999) Differential antitumor effects of administration of recombinant IL-18 or recombinant IL-12 are mediated primarily by Fas-Fas ligand- and perforin-induced tumor apoptosis, respectively. J Immunol 163:583
Hyodo Y, Matsui K, Hayashi N, Tsutsui H, Kashiwamura S, Yamauchi H, Hiroishi K, Takeda K, Tagawa Y, Iwakura Y, Kayagaki N, Kurimoto M, Okamura H, Hada T, Yagita H, Akira S, Nakanishi K, Higashino K (1999) IL-18 up-regulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor. J Immunol 162:1662
Jiang K, Zhong B, Gilvary DL, Corliss BC, Hong-Geller E, Wei S, Djeu JY (2000) Pivotal role of phosphoinositide-3 kinase in regulation of cytotoxicity in natural killer cells. Nat Immunol 1:419
Kalina U, Kauschat D, Koyama N, Nuernberger H, Ballas K, Koschmieder S, Bug G, Hofmann WK, Hoelzer D, Ottmann OG (2000) IL-18 activates STAT3 in the natural killer cell line 92, augments cytotoxic activity, and mediates IFN-γ production by the stress kinase p38 and by the extracellular regulated kinases p44erk-1 and p42erk-21. J Immunol 165:1307
Kämpfer H, Kalina U, Mühl H, Pfeilschifter J, Frank S (1999) Counterregulation of interleukin-18 mRNA and protein expression during cutaneous wound repair in mice. J Invest Dermatol 113:369
Kataoka T, Shinohara N, Takayama H, Takaku K, Kondo S, Yonehara S, Nagai K (1996) Concanamycin A, a powerful tool for characterization and estimation of contribution of perforin- and Fas-based lytic pathways in cell-mediated cytotoxicity. J Immunol 156:3678
Kayagaki N, Yamaguchi N, Nakayama M, Kawasaki A, Akiba H, Okumura K, Yagita H (1999) Involvement of TNF-related apoptosis-inducing ligand in human CD4+ T cell-mediated cytotoxicity. J Immunol 162:2639
Kim S, Iizuka K, Aguila HL, Weissman IL, Yokoyama WM (2000) In vivo natural killer cell activities revealed by natural killer cell-deficient mice. Proc Natl Acad Sci U S A 97:2731
Kurago ZB, Lutz CT, Smith KD, Colonna M (1998) NK cell natural cytotoxicity and IFN-γ production are not always coordinately regulated: engagement of DX9 KIR+ NK cells by HLA-B7 variants and target cells. J Immunol 160:1573
Landis SH, Murray T, Bolden S, Wingo PA (1998) Cancer statistics, 1998. CA Cancer J Clin 48:6
Lippman SM, Hong WK (1989) Second malignant tumors in head and neck squamous cell carcinoma: the overshadowing threat for patients with early-stage disease. Int J Radiat Oncol Biol Phys 17:691
Long EO (1999) Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 17:875
Lutz CT, Kurago ZB (1999) Human leukocyte antigen class I expression on squamous cell carcinoma cells regulates natural killer cell activity. Cancer Res 59:5793
Naik SM, Cannon G, Burbach GJ, Singh SR, Swerlick RA, Wilcox JN, Ansel JC, Caughman SW (1999) Human keratinocytes constitutively express interleukin-18 and secrete biologically active interleukin-18 after treatment with pro-inflammatory mediators and dinitrochlorobenzene. J Invest Dermatol 113:766
Pagès F, Berger A, Henglein B, Piqueras B, Danel C, Zinzindohoue F, Thiounn N, Cugnenc PH, Fridman WH (1999) Modulation of interleukin-18 expression in human colon carcinoma: consequences for tumor immune surveillance. Int J Cancer 84:326
Peritt D, Robertson S, Gri G, Showe L, Aste-Amezaga M, Trinchieri G (1998) Differentiation of human NK cells into NK1 and NK2 subsets. J Immunol 161:5821
Rabinowich H, Vitolo D, Altarac S, Herberman RB, Whiteside TL (1992) Role of cytokines in the adoptive immunotherapy of an experimental model of human head and neck cancer by human IL-2-activated natural killer cells. J Immunol 149:340
Rajagopalan S, Long EO (1999) A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. J Exp Med 189:1093
Rajagopalan S, Fu J, Long EO (2001) Cutting edge: induction of IFN-γ production but not cytotoxicity by the killer cell Ig-like receptor KIR2DL4 (CD158d) in resting NK cells. J Immunol 167:1877
Rossi D, Zlotnik A (2000) The biology of chemokines and their receptors. Annu Rev Immunol 18:217
Sacchi M, Vitolo D, Sedlmayr P, Rabinowich H, Johnson JT, Herberman RB, Whiteside TL (1991) Induction of tumor regression in experimental model of human head and neck cancer by human A-LAK cells and IL-2. Int J Cancer 47:784
Schantz SP, Ordonez NG (1991) Quantitation of natural killer cell function and risk of metastatic poorly differentiated head and neck cancer. Nat Immun Cell Growth Regul 10:278
Sgadari C, Angiolillo AL, Tosato G (1996) Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. Blood 87:3877
Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD (2001) IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107
Stoll S, Muller G, Kurimoto M, Saloga J, Tanimoto T, Yamauchi H, Okamura H, Knop J, Enk AH (1997) Production of IL-18 (IFN-gamma-inducing factor) messenger RNA and functional protein by murine keratinocytes. J Immunol 159:298
Sugawara S, Uehara A, Nochi T, Yamaguchi T, Ueda H, Sugiyama A, Hanzawa K, Kumagai K, Okamura H, Takada H (2001) Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion by human oral epithelial cells. J Immunol 167:6568
Takeuchi M, Nishizaki Y, Sano O, Ohta T, Ikeda M, Kurimoto M (1997) Immunohistochemical and immuno-electron-microscopic detection of interferon-γ-inducing factor ("interleukin-18") in mouse intestinal epithelial cells. Cell Tissue Res 289:499
Tay CH, Welsh RM (1997) Distinct organ-dependent mechanisms for the control of murine cytomegalovirus infection by natural killer cells. J Virol 71:267
Vitolo D, Ciocci L, Ferrauti P, Tiboni F, Cicerone E, Gallo A, De Vincentiis M, Baroni CD (2000) Interleukin-12-related cytokine gene expression in carcinomas of the breast, lung, and larynx: a study at tissue level. Cancer Detect Prev 24:422
Wang ZY, Gaggero A, Rubartelli A, Rosso O, Miotti S, Mezzanzanica D, Canevari S, Ferrini S (2002) Expression of interleukin-18 in human ovarian carcinoma and normal ovarian epithelium: evidence for defective processing in tumor cells. Int J Cancer 98:873
Yuan D, Koh CY, Wilder JA (1994) Interactions between B lymphocytes and NK cells. FASEB J 8:1012
Zamai L, Ahmad M, Bennett IM, Azzoni L, Alnemri ES, Perussia B (1998) Natural killer (NK) cell-mediated cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature primary human NK cells. J Exp Med 188:2375
Acknowledgements
We thank Chris Bromley for technical assistance and the National Cancer Institute for human rIL-2.
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This work was supported by National Institutes of Health grant DE11139.
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Moore, M.B., Kurago, Z.B., Fullenkamp, C.A. et al. Squamous cell carcinoma cells differentially stimulate NK cell effector functions: the role of IL-18. Cancer Immunol Immunother 52, 107–115 (2003). https://doi.org/10.1007/s00262-002-0361-8
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DOI: https://doi.org/10.1007/s00262-002-0361-8