Abstract
NK cells have been shown to play an important role in the lungs with regards to tumor cell clearance and resistance of this organ to metastases. Here, we have investigated whether NK cells play a similar role in organs other than the lungs. We conclude that while organ-resistance to metastases correlates well with the NK activity of the host, a clear correlation between NK activity and clearance of tumor cells is found only in the lungs. We also demonstrate that activation of NK cells with the TLR 3 ligand poly I:C results in a substantial increase in the number of organ-associated NK cells. This increase may explain the increased resistance to metastasis seen in many organs after poly I:C treatment. Finally, we present data showing that NK cells activated ex vivo with IL-2 are able to localize to lung tumors following iv adoptive transfer and to significantly reduce the tumors they infiltrate. We conclude that NK cells, which currently are under intense investigation owing to their newly discovered immunoregulatory functions, remain very potent antitumor killer cells capable of killing not only circulating tumor cells, but also well-established micro metastases.
Similar content being viewed by others
References
Coca S, Perez-Piqueras J, Martinez D, et al: The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer 1997; 79(12):2320–2328.
Ishigami S, Natsugoe S, Tokuda K, et al: Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 2000;88(3):577–583.
Villegas FR, Coca S, Villarrubia VG, et al: Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. Lung Cancer 2002;35(1):23–28.
Hsia JY, Chen JT, Chen CY, et al: Prognostic significance of intratumoral natural killer cells in primary resected esophageal squamous cell carcinoma. Chang Gung Med J 2005;28(5):335–340.
Trinchieri G: Biology of natural killer cells. Adv Immunol 1989;47:187–376.
Gorelik E, Bere WW, Herberman RB: Role of NK cells in the antimetastatic effect of anticoagulant drugs. Int J Cancer 1984;33(1):87–94.
Hanna N: Role of natural killer cells in control of cancer metastasis. Cancer Metastasis Rev 1982;1(1):45–64.
Riccardi C, Puccetti P, Santoni A, Herberman RB: Rapid in vivo assay of mouse natural killer cell activity. J Natl Cancer Inst 1979;63(4):1041–1045.
Talmadge JE, Adams J, Phillips H, et al: Immunotherapeutic potential in murine tumor models of polyinosinic-polycytidylic acid and poly-L-lysine solubilized by carboxymethylcellulose. Cancer Res 1985;45(3): 1066–1072.
Gorelik E, Fogel M, Feldman M, Segal S: Differences in resistance of metastatic tumor cells and cells from local tumor growth to cytotoxicity of natural killer cells. J Natl Cancer Inst 1979;63(6):1397–1404.
Wiltrout RH, Herberman RB, Zhang SR, et al: Role of organ-associated NK cells in decreased formation of experimental metastases in lung and liver. J Immunol 1985;134(6):4267–4275.
Wiltrout RH, Mathieson BJ, Talmadge JE, et al: Augmentation of organ-associated natural killer activity by biological response modifiers. Isolation and characterization of large granular lymphocytes from the liver. J Exp Med 1984;160(5):1431–1449.
Weiss L: Cancer cell traffic from the lungs to the liver: an example of metastatic inefficiency. Int J Cancer 1980;25(3):385–392.
Basse P, Hokland P, Heron I, Hokland M: Fate of tumor cells injected into left ventricle of heart in BALB/c mice: role of natural killer cells. J Natl Cancer Inst 1988; 80(9):657–665.
Basse PH, Hokland P, Gundersen HJ, Hokland M: Enumeration of organ-associated natural killer cells in mice: application of a new stereological method. Apmis 1992;100(3):202–208.
Wiltrout RH, et al: Augmentation of mouse liver-associated natural killer activity by biologic response modifiers occurs largely via rapid recruitment of large granular lymphocytes from the bone marrow. J Immunol 1989;143(1):372–378.
Gunji Y, Vujanovic NL, Hiserodt JC, Herberman RB, Gorelik E: Generation and characterization of purified adherent lymphokine-activated killer cells in mice. J Immunol 1989;142(5):1748–1754.
Vujanovic NL, Herberman RB, Maghazachi AA, Hiserodt JC: Lymphokine-activated killer cells in rats. III. A simple method for the purification of large granular lymphocytes and their rapid expansion and conversion into lymphokine-activated killer cells. J Exp Med 1988;167(1):15–29.
Basse P, Herberman RB, Nannmark U, et al: Accumulation of adoptively transferred adherent, lymphokine-activated killer cells in murine metastases. J Exp Med 1991;174(2):479–488.
Basse PH, Nannmark U, Johansson BR, Herberman RB, Goldfarb RH: Establishment of cell-to-cell contact by adoptively transferred adherent lymphokine-activated killer cells with metastatic murine melanoma cells. J Natl Cancer Inst 1991;83(13):944–950.
Basse PH: Tissue distribution of natural killer cells and their role in clearance and metastasis of tumor cells. (PhD). University of Aarhus, DK; 1992.
Basse PH, Goldfarb RH, Herberman RB, Hokland ME: Accumulation of adoptively transferred A-NK cells in murine metastases: kinetics and role of interleukin-3. In Vivo 1994;8(1):17–24.
Basse PH: Tissue distribution and tumor localization of effector cells in adoptive immunotherapy of cancer. APMIS Suppl 1995;55:1–28.
Yang Q, Hokland ME, Bryant JL, et al: Tumor-localization by adoptively transferred, interleukin-2-activated NK cells leads to destruction of well-established lung metastases. Int J Cancer 2003;105(4):512–519.
Hagenaars M, Ensink NG, Basse PH, et al: The microscopic anatomy of experimental rat CC531 colon tumour metastases: consequences for immunotherapy? Clin Exp Metastasis 2000;18(2):189–196.
Kuppen PJ, van der Eb MM, Jonges LE, et al: Tumor structure and extracellular matrix as a possible barrier for therapeutic approaches using immune cells or aden-oviruses in colorectal cancer. Histochem Cell Biol 2001;115(1):67–72.
Nannmark U, Basse P, Johansson BR, Kuppen P, Kjergaard J, Hokland M: Morphological studies of effector cell-microvessel interactions in adoptive immunotherapy in tumor-bearing animals. Nat Immun 1996;15(2–3): 78–86.
Nannmark U, Hokland ME, Agger R, et al: Tumor blood supply and tumor localization by adoptively transferred IL-2 activated natural killer cells. In Vivo 2000;14(5):651–658.
Nannmark U, Johansson BR, Bryant JL, et al: Microvessel origin and distribution in pulmonary metastases of B16 melanoma: implication for adoptive immunotherapy. Cancer Res 1995;55(20):4627–4632.
Yang Q, Goding S, Hagenaars M, et al: Morphological appearance, content of extracellular matrix and vascular density of lung metastases predicts permissiveness to infiltration by adoptively transferred natural killer and T cells. Cancer Immunol Immunother 2005:1–9.
Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C: Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 2002;195(3): 343–351.
Piccioli D, Sbrana S, Melandri E, Valiante NM: Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med 2002;195(3): 335–341.
Zitvogel L: Dendritic and natural killer cells cooperate in the control/switch of innate immunity. J Exp Med 2002;195(3):F9–14.
Kalinski P, Giermasz A, Nakamura Y, et al: Helper role of NK cells during the induction of anticancer responses by dendritic cells. Mol Immunol 2005;42(4): 535–539.
Kalinski P, Mailliard RB, Giermasz A, et al: Natural killer-dendritic cell cross-talk in cancer immunotherapy. Expert Opin Biol Ther 2005;5(10):1303–1315.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Yang, Q., Goding, S.R., Hokland, M.E. et al. Antitumor activity of NK cells. Immunol Res 36, 13–25 (2006). https://doi.org/10.1385/IR:36:1:13
Issue Date:
DOI: https://doi.org/10.1385/IR:36:1:13