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. 1996 Aug 1;184(2):579–584. doi: 10.1084/jem.184.2.579

Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism

PMCID: PMC2192723  PMID: 8760811

Abstract

Interleukin-10 (IL-10) is a recently described pleiotropic cytokine secreted mainly by type 2 helper T cells. Previous studies have shown that IL-10 suppresses cytokine expression by natural killer (NK) and type 1 T cells, thus down-regulating cell-mediated immunity and stimulating humoral responses. We here report that injected IL-10 protein is an efficient inhibitor of tumor metastasis in experimental (B16-F10) and spontaneous (M27 and Lox human melanoma) metastasis models in vivo at doses that do not have toxic effects on normal or cancer cells. Histological characterization after IL-10 treatment confirmed the absence of CD8+ and CD4+ T cells and macrophages at the sites of tumor growth, but abundant NK cells were localized at these sites. This unexpected finding was confirmed by showing that IL-10 inhibits most B16-F10 and Lox metastases in mice deficient in T or B cells (SCID and nu/nu mice), but not in those deficient in NK cells (beige mice or NK cell-depleted mice). However, IL-10 downregulation of pro-inflammatory cytokine production and/or recruitment of additional effector cells may also be involved in the anti-tumor effect at higher local concentrations of IL-10, since transfected B16 tumor cells expressing high amounts of IL-10 were rejected by normal, nu/nu, or SCID mice at the primary tumor stage, and there was still a 33% inhibition of tumor metastasis in beige mice.

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Selected References

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  1. Alleva D. G., Elgert K. D. Promotion of macrophage-stimulated autoreactive T cell proliferation by interleukin-10: counteraction of macrophage suppressor activity during tumor growth. Immunobiology. 1995 Feb;192(3-4):155–171. doi: 10.1016/S0171-2985(11)80094-X. [DOI] [PubMed] [Google Scholar]
  2. Beissert S., Hosoi J., Grabbe S., Asahina A., Granstein R. D. IL-10 inhibits tumor antigen presentation by epidermal antigen-presenting cells. J Immunol. 1995 Feb 1;154(3):1280–1286. [PubMed] [Google Scholar]
  3. Bejarano M. T., de Waal Malefyt R., Abrams J. S., Bigler M., Bacchetta R., de Vries J. E., Roncarolo M. G. Interleukin 10 inhibits allogeneic proliferative and cytotoxic T cell responses generated in primary mixed lymphocyte cultures. Int Immunol. 1992 Dec;4(12):1389–1397. doi: 10.1093/intimm/4.12.1389. [DOI] [PubMed] [Google Scholar]
  4. Bermudez L. E., Champsi J. Infection with Mycobacterium avium induces production of interleukin-10 (IL-10), and administration of anti-IL-10 antibody is associated with enhanced resistance to infection in mice. Infect Immun. 1993 Jul;61(7):3093–3097. doi: 10.1128/iai.61.7.3093-3097.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blankenstein T., Qin Z. H., Uberla K., Müller W., Rosen H., Volk H. D., Diamantstein T. Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer. J Exp Med. 1991 May 1;173(5):1047–1052. doi: 10.1084/jem.173.5.1047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Blankenstein T., Rowley D. A., Schreiber H. Cytokines and cancer: experimental systems. Curr Opin Immunol. 1991 Oct;3(5):694–698. doi: 10.1016/0952-7915(91)90098-l. [DOI] [PubMed] [Google Scholar]
  7. Bogdan C., Vodovotz Y., Nathan C. Macrophage deactivation by interleukin 10. J Exp Med. 1991 Dec 1;174(6):1549–1555. doi: 10.1084/jem.174.6.1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Burrows F. J., Haskard D. O., Hart I. R., Marshall J. F., Selkirk S., Poole S., Thorpe P. E. Influence of tumor-derived interleukin 1 on melanoma-endothelial cell interactions in vitro. Cancer Res. 1991 Sep 15;51(18):4768–4775. [PubMed] [Google Scholar]
  9. Carson W. E., Lindemann M. J., Baiocchi R., Linett M., Tan J. C., Chou C. C., Narula S., Caligiuri M. A. The functional characterization of interleukin-10 receptor expression on human natural killer cells. Blood. 1995 Jun 15;85(12):3577–3585. [PubMed] [Google Scholar]
  10. Denis M., Ghadirian E. IL-10 neutralization augments mouse resistance to systemic Mycobacterium avium infections. J Immunol. 1993 Nov 15;151(10):5425–5430. [PubMed] [Google Scholar]
  11. Ding L., Linsley P. S., Huang L. Y., Germain R. N., Shevach E. M. IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression. J Immunol. 1993 Aug 1;151(3):1224–1234. [PubMed] [Google Scholar]
  12. Dranoff G., Jaffee E., Lazenby A., Golumbek P., Levitsky H., Brose K., Jackson V., Hamada H., Pardoll D., Mulligan R. C. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3539–3543. doi: 10.1073/pnas.90.8.3539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fearon E. R., Pardoll D. M., Itaya T., Golumbek P., Levitsky H. I., Simons J. W., Karasuyama H., Vogelstein B., Frost P. Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell. 1990 Feb 9;60(3):397–403. doi: 10.1016/0092-8674(90)90591-2. [DOI] [PubMed] [Google Scholar]
  14. Giovarelli M., Musiani P., Modesti A., Dellabona P., Casorati G., Allione A., Consalvo M., Cavallo F., di Pierro F., De Giovanni C. Local release of IL-10 by transfected mouse mammary adenocarcinoma cells does not suppress but enhances antitumor reaction and elicits a strong cytotoxic lymphocyte and antibody-dependent immune memory. J Immunol. 1995 Sep 15;155(6):3112–3123. [PubMed] [Google Scholar]
  15. Go N. F., Castle B. E., Barrett R., Kastelein R., Dang W., Mosmann T. R., Moore K. W., Howard M. Interleukin 10, a novel B cell stimulatory factor: unresponsiveness of X chromosome-linked immunodeficiency B cells. J Exp Med. 1990 Dec 1;172(6):1625–1631. doi: 10.1084/jem.172.6.1625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hock H., Dorsch M., Diamantstein T., Blankenstein T. Interleukin 7 induces CD4+ T cell-dependent tumor rejection. J Exp Med. 1991 Dec 1;174(6):1291–1298. doi: 10.1084/jem.174.6.1291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hock H., Dorsch M., Kunzendorf U., Qin Z., Diamantstein T., Blankenstein T. Mechanisms of rejection induced by tumor cell-targeted gene transfer of interleukin 2, interleukin 4, interleukin 7, tumor necrosis factor, or interferon gamma. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2774–2778. doi: 10.1073/pnas.90.7.2774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kharkevitch D. D., Seito D., Balch G. C., Maeda T., Balch C. M., Itoh K. Characterization of autologous tumor-specific T-helper 2 cells in tumor-infiltrating lymphocytes from a patient with metastatic melanoma. Int J Cancer. 1994 Aug 1;58(3):317–323. doi: 10.1002/ijc.2910580302. [DOI] [PubMed] [Google Scholar]
  19. Moore K. W., O'Garra A., de Waal Malefyt R., Vieira P., Mosmann T. R. Interleukin-10. Annu Rev Immunol. 1993;11:165–190. doi: 10.1146/annurev.iy.11.040193.001121. [DOI] [PubMed] [Google Scholar]
  20. Moses H. L., Yang E. Y., Pietenpol J. A. TGF-beta stimulation and inhibition of cell proliferation: new mechanistic insights. Cell. 1990 Oct 19;63(2):245–247. doi: 10.1016/0092-8674(90)90155-8. [DOI] [PubMed] [Google Scholar]
  21. Nabioullin R., Sone S., Mizuno K., Yano S., Nishioka Y., Haku T., Ogura T. Interleukin-10 is a potent inhibitor of tumor cytotoxicity by human monocytes and alveolar macrophages. J Leukoc Biol. 1994 Apr;55(4):437–442. doi: 10.1002/jlb.55.4.437. [DOI] [PubMed] [Google Scholar]
  22. Rice G. E., Bevilacqua M. P. An inducible endothelial cell surface glycoprotein mediates melanoma adhesion. Science. 1989 Dec 8;246(4935):1303–1306. doi: 10.1126/science.2588007. [DOI] [PubMed] [Google Scholar]
  23. Richter G., Krüger-Krasagakes S., Hein G., Hüls C., Schmitt E., Diamantstein T., Blankenstein T. Interleukin 10 transfected into Chinese hamster ovary cells prevents tumor growth and macrophage infiltration. Cancer Res. 1993 Sep 15;53(18):4134–4137. [PubMed] [Google Scholar]
  24. Roth C., Mir L. M., Cressent M., Quintin-Colonna F., Ley V., Fradelizi D., Kourilsky P. Inhibition of tumor growth by histoincompatible cells expressing interleukin-2. Int Immunol. 1992 Dec;4(12):1429–1436. doi: 10.1093/intimm/4.12.1429. [DOI] [PubMed] [Google Scholar]
  25. Salazar-Onfray F., Petersson M., Franksson L., Matsuda M., Blankenstein T., Kärre K., Kiessling R. IL-10 converts mouse lymphoma cells to a CTL-resistant, NK-sensitive phenotype with low but peptide-inducible MHC class I expression. J Immunol. 1995 Jun 15;154(12):6291–6298. [PubMed] [Google Scholar]
  26. Silagi S., Dutkowski R., Schaefer A. Eradication of mouse melanoma by combined treatment with recombinant human interleukin 2 and recombinant murine interferon-gamma. Int J Cancer. 1988 Feb 15;41(2):315–322. doi: 10.1002/ijc.2910410225. [DOI] [PubMed] [Google Scholar]
  27. Silva J. S., Morrissey P. J., Grabstein K. H., Mohler K. M., Anderson D., Reed S. G. Interleukin 10 and interferon gamma regulation of experimental Trypanosoma cruzi infection. J Exp Med. 1992 Jan 1;175(1):169–174. doi: 10.1084/jem.175.1.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sulitzeanu D. Immunosuppressive factors in human cancer. Adv Cancer Res. 1993;60:247–267. doi: 10.1016/s0065-230x(08)60827-1. [DOI] [PubMed] [Google Scholar]
  29. Tepper R. I., Pattengale P. K., Leder P. Murine interleukin-4 displays potent anti-tumor activity in vivo. Cell. 1989 May 5;57(3):503–512. doi: 10.1016/0092-8674(89)90925-2. [DOI] [PubMed] [Google Scholar]
  30. Tripp C. S., Wolf S. F., Unanue E. R. Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3725–3729. doi: 10.1073/pnas.90.8.3725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Van Vlasselaer P., Borremans B., van Gorp U., Dasch J. R., De Waal-Malefyt R. Interleukin 10 inhibits transforming growth factor-beta (TGF-beta) synthesis required for osteogenic commitment of mouse bone marrow cells. J Cell Biol. 1994 Feb;124(4):569–577. doi: 10.1083/jcb.124.4.569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Weber J. S., Jay G., Tanaka K., Rosenberg S. A. Immunotherapy of a murine tumor with interleukin 2. Increased sensitivity after MHC class I gene transfection. J Exp Med. 1987 Dec 1;166(6):1716–1733. doi: 10.1084/jem.166.6.1716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Yamada G., Kitamura Y., Sonoda H., Harada H., Taki S., Mulligan R. C., Osawa H., Diamantstein T., Yokoyama S., Taniguchi T. Retroviral expression of the human IL-2 gene in a murine T cell line results in cell growth autonomy and tumorigenicity. EMBO J. 1987 Sep;6(9):2705–2709. doi: 10.1002/j.1460-2075.1987.tb02563.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Zheng L. M., Ojcius D. M., Young J. D. Distribution of perforin-containing cells in normal and pregnant mice. Eur J Immunol. 1993 Sep;23(9):2085–2091. doi: 10.1002/eji.1830230907. [DOI] [PubMed] [Google Scholar]
  35. de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. doi: 10.1084/jem.174.5.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. de Waal Malefyt R., Haanen J., Spits H., Roncarolo M. G., te Velde A., Figdor C., Johnson K., Kastelein R., Yssel H., de Vries J. E. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991 Oct 1;174(4):915–924. doi: 10.1084/jem.174.4.915. [DOI] [PMC free article] [PubMed] [Google Scholar]

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