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. 1999 Sep 24;79(1):119–130. doi: 10.1038/sj.bjc.6690021

Renal cell carcinoma induces interleukin 10 and prostaglandin E2 production by monocytes

C Ménétrier-Caux 1, C Bain 2, M C Favrot 2, A Duc 1, J Y Blay 1
PMCID: PMC2362183  PMID: 10408703

Abstract

Immunotherapy with interleukin 2 (IL-2) is not an effective anti-cancer treatment in the majority of patients with renal cell carcinoma (RCC), suggesting that the activation of cytotoxic T cells or NK cells may be impaired in vivo in these patients. The production of immunosuppressive factors by RCC was investigated. Using immunohistochemistry, IL-10 was detectable in 10 of 21 tumour samples tested. IL-10 was undetectable in the supernatant of cell lines derived from these RCCs. However, these cell lines or their conditioned medium (RCC CM), but not normal renal epithelial cells adjacent to the RCC or breastcarcinoma cell lines, were found to induce IL-10, as well as prostaglandin E2 (PGE2) and tumour necrosis factor (TNF)α production by autologous or allogeneic peripheral blood mononuclear cells (PBMCs) and monocytes. IL-10 production induced by RCC CM was found to be dependent on TNF-α and PGE2 since an anti-TNF-α antibody (Ab) inhibited 40–70% of IL-10 production by monocytes, and the combination of anti-TNF-α Ab and indomethacin, an inhibitor of PGE2 production, inhibited 80–94% of RCC CM-induced IL-10 production by monocytes. The RCC CM of the five cell lines tested were found to induce a down-regulation of the expression of HLA-DR and CD86, as well as a strong inhibition of mannose receptor-dependent endocytosis by monocytes. The blockade of HLA-DR and CD86 expression was partially abrogated by indomethacin and anti-IL-10 Ab respectively, and completely abrogated by an anti-TNF-α Ab. The inhibition of mannose receptor-dependent endocytosis was partially abrogated by an anti-IL-10 Ab and completely abrogated by an anti-TNF-α Ab. These esults indicate that RCCs induce IL-10, PGE2 and TNF-α production by monocytes, which down-regulate the expression of cell-surface molecules involved in antigen presentation as well as their endocytic capacity. © 1999 Cancer Research Campaign

Keywords: interleukin 10, prostaglandin E2, tumour necrosis factor α, renal cell carcinoma, immunosuppression

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Selected References

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  1. Abrams J. S., Roncarolo M. G., Yssel H., Andersson U., Gleich G. J., Silver J. E. Strategies of anti-cytokine monoclonal antibody development: immunoassay of IL-10 and IL-5 in clinical samples. Immunol Rev. 1992 Jun;127:5–24. doi: 10.1111/j.1600-065x.1992.tb01406.x. [DOI] [PubMed] [Google Scholar]
  2. Alleva D. G., Burger C. J., Elgert K. D. Tumor-induced macrophage tumor necrosis factor-alpha production suppresses autoreactive T cell proliferation. Immunobiology. 1993 Aug;188(4-5):430–445. doi: 10.1016/s0171-2985(11)80225-1. [DOI] [PubMed] [Google Scholar]
  3. Bachwich P. R., Chensue S. W., Larrick J. W., Kunkel S. L. Tumor necrosis factor stimulates interleukin-1 and prostaglandin E2 production in resting macrophages. Biochem Biophys Res Commun. 1986 Apr 14;136(1):94–101. doi: 10.1016/0006-291x(86)90881-8. [DOI] [PubMed] [Google Scholar]
  4. Bain C., Merrouche Y., Puisieux I., Duc A., Colombo M. P., Favrot M. B7.1 gene transduction of human renal-cell-carcinoma cell lines restores the proliferative response and cytotoxic function of allogeneic T cells. Int J Cancer. 1996 Sep 17;67(6):769–776. doi: 10.1002/(SICI)1097-0215(19960917)67:6<769::AID-IJC4>3.0.CO;2-P. [DOI] [PubMed] [Google Scholar]
  5. Benjamin D., Knobloch T. J., Dayton M. A. Human B-cell interleukin-10: B-cell lines derived from patients with acquired immunodeficiency syndrome and Burkitt's lymphoma constitutively secrete large quantities of interleukin-10. Blood. 1992 Sep 1;80(5):1289–1298. [PubMed] [Google Scholar]
  6. Blay J. Y., Burdin N., Rousset F., Lenoir G., Biron P., Philip T., Banchereau J., Favrot M. C. Serum interleukin-10 in non-Hodgkin's lymphoma: a prognostic factor. Blood. 1993 Oct 1;82(7):2169–2174. [PubMed] [Google Scholar]
  7. Capsoni F., Minonzio F., Ongari A. M., Carbonelli V., Galli A., Zanussi C. IL-10 up-regulates human monocyte phagocytosis in the presence of IL-4 and IFN-gamma. J Leukoc Biol. 1995 Sep;58(3):351–358. doi: 10.1002/jlb.58.3.351. [DOI] [PubMed] [Google Scholar]
  8. Cohen P. J., Lotze M. T., Roberts J. R., Rosenberg S. A., Jaffe E. S. The immunopathology of sequential tumor biopsies in patients treated with interleukin-2. Correlation of response with T-cell infiltration and HLA-DR expression. Am J Pathol. 1987 Nov;129(2):208–216. [PMC free article] [PubMed] [Google Scholar]
  9. Combaret V., Wang Q., Favrot M. C., Thiesse P., Philip I., Bouffet E., Bailly C., Bouvier R., Chauvin F., Zucker J. M. Clinical value of N-myc oncogene amplification in 52 patients with neuroblastoma included in recent therapeutic protocols. Eur J Cancer Clin Oncol. 1989 Nov;25(11):1607–1612. doi: 10.1016/0277-5379(89)90305-2. [DOI] [PubMed] [Google Scholar]
  10. Emilie D., Touitou R., Raphael M., Peuchmaur M., Devergnee O., Rea D., Coumbraras J., Crevon M. C., Edelman L., Joab I. In vivo production of interleukin-10 by malignant cells in AIDS lymphomas. Eur J Immunol. 1992 Nov;22(11):2937–2942. doi: 10.1002/eji.1830221127. [DOI] [PubMed] [Google Scholar]
  11. Filgueira L., Zuber M., Merlo A., Caetano V., Schultz E., Harder F., Spagnoli G. C., Heberer M. Cytokine gene transcription in renal cell carcinoma. Br J Surg. 1993 Oct;80(10):1322–1325. doi: 10.1002/bjs.1800801034. [DOI] [PubMed] [Google Scholar]
  12. Fiorentino D. F., Zlotnik A., Vieira P., Mosmann T. R., Howard M., Moore K. W., O'Garra A. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol. 1991 May 15;146(10):3444–3451. [PubMed] [Google Scholar]
  13. Gastl G. A., Abrams J. S., Nanus D. M., Oosterkamp R., Silver J., Liu F., Chen M., Albino A. P., Bander N. H. Interleukin-10 production by human carcinoma cell lines and its relationship to interleukin-6 expression. Int J Cancer. 1993 Aug 19;55(1):96–101. doi: 10.1002/ijc.2910550118. [DOI] [PubMed] [Google Scholar]
  14. Groux H., O'Garra A., Bigler M., Rouleau M., Antonenko S., de Vries J. E., Roncarolo M. G. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997 Oct 16;389(6652):737–742. doi: 10.1038/39614. [DOI] [PubMed] [Google Scholar]
  15. Hashimoto S., Yamada M., Motoyoshi K., Akagawa K. S. Enhancement of macrophage colony-stimulating factor-induced growth and differentiation of human monocytes by interleukin-10. Blood. 1997 Jan 1;89(1):315–321. [PubMed] [Google Scholar]
  16. Howard M., O'Garra A. Biological properties of interleukin 10. Immunol Today. 1992 Jun;13(6):198–200. doi: 10.1016/0167-5699(92)90153-X. [DOI] [PubMed] [Google Scholar]
  17. Huang M., Sharma S., Mao J. T., Dubinett S. M. Non-small cell lung cancer-derived soluble mediators and prostaglandin E2 enhance peripheral blood lymphocyte IL-10 transcription and protein production. J Immunol. 1996 Dec 15;157(12):5512–5520. [PubMed] [Google Scholar]
  18. Kambayashi T., Alexander H. R., Fong M., Strassmann G. Potential involvement of IL-10 in suppressing tumor-associated macrophages. Colon-26-derived prostaglandin E2 inhibits TNF-alpha release via a mechanism involving IL-10. J Immunol. 1995 Apr 1;154(7):3383–3390. [PubMed] [Google Scholar]
  19. Lehmmann V., Benninghoff B., Dröge W. Tumor necrosis factor-induced activation of peritoneal macrophages is regulated by prostaglandin E2 and cAMP. J Immunol. 1988 Jul 15;141(2):587–591. [PubMed] [Google Scholar]
  20. Maeurer M. J., Martin D. M., Castelli C., Elder E., Leder G., Storkus W. J., Lotze M. T. Host immune response in renal cell cancer: interleukin-4 (IL-4) and IL-10 mRNA are frequently detected in freshly collected tumor-infiltrating lymphocytes. Cancer Immunol Immunother. 1995 Aug;41(2):111–121. doi: 10.1007/BF01527407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nakagomi H., Pisa P., Pisa E. K., Yamamoto Y., Halapi E., Backlin K., Juhlin C., Kiessling R. Lack of interleukin-2 (IL-2) expression and selective expression of IL-10 mRNA in human renal cell carcinoma. Int J Cancer. 1995 Nov 3;63(3):366–371. doi: 10.1002/ijc.2910630311. [DOI] [PubMed] [Google Scholar]
  22. Oosterwijk E., Ruiter D. J., Hoedemaeker P. J., Pauwels E. K., Jonas U., Zwartendijk J., Warnaar S. O. Monoclonal antibody G 250 recognizes a determinant present in renal-cell carcinoma and absent from normal kidney. Int J Cancer. 1986 Oct 15;38(4):489–494. doi: 10.1002/ijc.2910380406. [DOI] [PubMed] [Google Scholar]
  23. Pisa P., Halapi E., Pisa E. K., Gerdin E., Hising C., Bucht A., Gerdin B., Kiessling R. Selective expression of interleukin 10, interferon gamma, and granulocyte-macrophage colony-stimulating factor in ovarian cancer biopsies. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7708–7712. doi: 10.1073/pnas.89.16.7708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rosenberg S. A., Lotze M. T., Yang J. C., Linehan W. M., Seipp C., Calabro S., Karp S. E., Sherry R. M., Steinberg S., White D. E. Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer. J Clin Oncol. 1989 Dec;7(12):1863–1874. doi: 10.1200/JCO.1989.7.12.1863. [DOI] [PubMed] [Google Scholar]
  25. Rubin J. T., Elwood L. J., Rosenberg S. A., Lotze M. T. Immunohistochemical correlates of response to recombinant interleukin-2-based immunotherapy in humans. Cancer Res. 1989 Dec 15;49(24 Pt 1):7086–7092. [PubMed] [Google Scholar]
  26. Sallusto F., Cella M., Danieli C., Lanzavecchia A. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J Exp Med. 1995 Aug 1;182(2):389–400. doi: 10.1084/jem.182.2.389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sallusto F., Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med. 1994 Apr 1;179(4):1109–1118. doi: 10.1084/jem.179.4.1109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Taga K., Mostowski H., Tosato G. Human interleukin-10 can directly inhibit T-cell growth. Blood. 1993 Jun 1;81(11):2964–2971. [PubMed] [Google Scholar]
  29. Voorzanger N., Touitou R., Garcia E., Delecluse H. J., Rousset F., Joab I., Favrot M. C., Blay J. Y. Interleukin (IL)-10 and IL-6 are produced in vivo by non-Hodgkin's lymphoma cells and act as cooperative growth factors. Cancer Res. 1996 Dec 1;56(23):5499–5505. [PubMed] [Google Scholar]
  30. Wang Q., Redovan C., Tubbs R., Olencki T., Klein E., Kudoh S., Finke J., Bukowski R. M. Selective cytokine gene expression in renal cell carcinoma tumor cells and tumor-infiltrating lymphocytes. Int J Cancer. 1995 Jun 9;61(6):780–785. doi: 10.1002/ijc.2910610607. [DOI] [PubMed] [Google Scholar]
  31. Wanidworanun C., Strober W. Predominant role of tumor necrosis factor-alpha in human monocyte IL-10 synthesis. J Immunol. 1993 Dec 15;151(12):6853–6861. [PubMed] [Google Scholar]
  32. Watts C. Capture and processing of exogenous antigens for presentation on MHC molecules. Annu Rev Immunol. 1997;15:821–850. doi: 10.1146/annurev.immunol.15.1.821. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. de Waal Malefyt R., Yssel H., de Vries J. E. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol. 1993 Jun 1;150(11):4754–4765. [PubMed] [Google Scholar]

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