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. 1994 Oct;70(4):625–630. doi: 10.1038/bjc.1994.361

Interleukin 1 beta synergises with interleukin 2 in the outgrowth of autologous tumour-reactive CD8+ effectors.

C N Baxevanis 1, G V Dedoussis 1, A D Gritzapis 1, G P Stathopoulos 1, M Papamichail 1
PMCID: PMC2033388  PMID: 7917907

Abstract

Using peritoneal fluid or pleural effusion obtained from 20 patients with lung, ovarian or metastatic breast cancer, we separated tumour cells from malignant effusion-associated mononuclear cells (MEMNCs) using discontinuous Ficoll-Hypaque density gradients. CD3+ T lymphocytes represented the main population of MEMNCs. The mean +/- s.d. CD4/CD8 ratio of MEMNC suspensions was 1.18 +/- 0.40. MEMNCs proliferated and expanded in vitro with human interleukin 2 (IL-2) either as CD3+ CD8+ cells or as CD3+ CD4+ cells or as mixed populations of CD8+ and CD4+ cells. Preferential cytolytic activity against autologous tumour cells was demonstrated in IL-2-activated MEMNC cultures with excess CD3+ CD8+ cells. In contrast, effectors derived from IL-2-activated cultures with excess CD3+ CD4+ cells lysed both autologous and allogeneic tumour target cells. The addition on day 0 of interleukin 1 beta (IL-1 beta) to MEMNCs cultured in the presence of IL-2 was effective in promoting the growth of CD3+ CD8+ cells and augmenting the cytotoxicity against autologous tumour. Simultaneously, the production of gamma-interferon (IFN-gamma) was increased in these cultures. This is the first report suggesting that IL-1 beta synergises with IL-2 to induce autologous tumour-specific CD8+ cytotoxic T lymphocytes (CTLs) within the MEMNC population. Selective enrichment in T-cell subsets by IL-1 beta may be useful in cellular adoptive immunotherapy using cells isolated from malignant effusions.

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Selected References

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  1. Baxevanis C. N., Papamichail M. Characterization of the anti-tumor immune response in human cancers and strategies for immunotherapy. Crit Rev Oncol Hematol. 1994 Jun;16(3):157–179. doi: 10.1016/1040-8428(94)90069-8. [DOI] [PubMed] [Google Scholar]
  2. Baxevanis C. N., Reclos G. J., Gritzapis A. D., Dedousis G. V., Arsenis P., Katsiyiannis A., Mitsis P. G., Tsavaris N., Papamichail M. Comparison of immune parameters in patients with one or two primary malignant neoplasms. Nat Immun. 1993 Jan-Feb;12(1):41–49. [PubMed] [Google Scholar]
  3. Baxevanis C. N., Reclos G. J., Gritzapis A. D., Dedousis G. V., Missitzis I., Papamichail M. Elevated prostaglandin E2 production by monocytes is responsible for the depressed levels of natural killer and lymphokine-activated killer cell function in patients with breast cancer. Cancer. 1993 Jul 15;72(2):491–501. doi: 10.1002/1097-0142(19930715)72:2<491::aid-cncr2820720227>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]
  4. Baxevanis C. N., Thanos D., Reclos G. J., Anastasopoulos E., Tsokos G. C., Papamatheakis J., Papamichail M. Prothymosin alpha enhances human and murine MHC class II surface antigen expression and messenger RNA accumulation. J Immunol. 1992 Apr 1;148(7):1979–1984. [PubMed] [Google Scholar]
  5. Blanchard D. K., Kavanagh J. J., Sinkovics J. G., Cavanagh D., Hewitt S. M., Djeu J. Y. Infiltration of interleukin-2-inducible killer cells in ascitic fluid and pleural effusions of advanced cancer patients. Cancer Res. 1988 Nov 15;48(22):6321–6327. [PubMed] [Google Scholar]
  6. Carrel S., Schmidt-Kessen A., Giuffrè L. Recombinant interferon-gamma can induce the expression of HLA-DR and -DC on DR-negative melanoma cells and enhance the expression of HLA-ABC and tumor-associated antigens. Eur J Immunol. 1985 Feb;15(2):118–123. doi: 10.1002/eji.1830150204. [DOI] [PubMed] [Google Scholar]
  7. Chen L. K., Mathieu-Mahul D., Bach F. H., Dausset J., Bensussan A., Sasportes M. Recombinant interferon alpha can induce rearrangement of T-cell antigen receptor alpha-chain genes and maturation to cytotoxicity in T-lymphocyte clones in vitro. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4887–4889. doi: 10.1073/pnas.83.13.4887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cozzolino F., Torcia M., Carossino A. M., Giordani R., Selli C., Talini G., Reali E., Novelli A., Pistoia V., Ferrarini M. Characterization of cells from invaded lymph nodes in patients with solid tumors. Lymphokine requirement for tumor-specific lymphoproliferative response. J Exp Med. 1987 Aug 1;166(2):303–318. doi: 10.1084/jem.166.2.303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Crump W. L., 3rd, Owen-Schaub L. B., Grimm E. A. Synergy of human recombinant interleukin 1 with interleukin 2 in the generation of lymphokine-activated killer cells. Cancer Res. 1989 Jan 1;49(1):149–153. [PubMed] [Google Scholar]
  10. Falkoff R. J., Butler J. L., Dinarello C. A., Fauci A. S. Direct effects of a monoclonal B cell differentiation factor and of purified interleukin 1 on B cell differentiation. J Immunol. 1984 Aug;133(2):692–696. [PubMed] [Google Scholar]
  11. Ferrini S., Biassoni R., Moretta A., Bruzzone M., Nicolin A., Moretta L. Clonal analysis of T lymphocytes isolated from ovarian carcinoma ascitic fluid. Phenotypic and functional characterization of T-cell clones capable of lysing autologous carcinoma cells. Int J Cancer. 1985 Sep 15;36(3):337–343. [PubMed] [Google Scholar]
  12. Forni G., Musso T., Jemma C., Boraschi D., Tagliabue A., Giovarelli M. Lymphokine-activated tumor inhibition in mice. Ability of a nonapeptide of the human IL-1 beta to recruit anti-tumor reactivity in recipient mice. J Immunol. 1989 Jan 15;142(2):712–718. [PubMed] [Google Scholar]
  13. Freimuth W. W., Depper J. M., Nabel G. J. Regulation of the IL-2 receptor alpha-gene. Interaction of a kappa B binding protein with cell-specific transcription factors. J Immunol. 1989 Nov 1;143(9):3064–3068. [PubMed] [Google Scholar]
  14. Garnick M. B., Reich S. D., Maxwell B., Coval-Goldsmith S., Richie J. P., Rudnick S. A. Phase I/II study of recombinant interferon gamma in advanced renal cell carcinoma. J Urol. 1988 Feb;139(2):251–255. doi: 10.1016/s0022-5347(17)42379-2. [DOI] [PubMed] [Google Scholar]
  15. Gromo G., Geller R. L., Inverardi L., Bach F. H. Signal requirements in the step-wise functional maturation of cytotoxic T lymphocytes. Nature. 1987 Jun 4;327(6121):424–426. doi: 10.1038/327424a0. [DOI] [PubMed] [Google Scholar]
  16. Hannet I., Erkeller-Yuksel F., Lydyard P., Deneys V., DeBruyère M. Developmental and maturational changes in human blood lymphocyte subpopulations. Immunol Today. 1992 Jun;13(6):215–218. doi: 10.1016/0167-5699(92)90157-3. [DOI] [PubMed] [Google Scholar]
  17. Heo D. S., Whiteside T. L., Kanbour A., Herberman R. B. Lymphocytes infiltrating human ovarian tumors. I. Role of Leu-19 (NKH1)-positive recombinant IL-2-activated cultures of lymphocytes infiltrating human ovarian tumors. J Immunol. 1988 Jun 1;140(11):4042–4049. [PubMed] [Google Scholar]
  18. Ioannides C. G., Freedman R. S., Platsoucas C. D., Rashed S., Kim Y. P. Cytotoxic T cell clones isolated from ovarian tumor-infiltrating lymphocytes recognize multiple antigenic epitopes on autologous tumor cells. J Immunol. 1991 Mar 1;146(5):1700–1707. [PubMed] [Google Scholar]
  19. Ioannides C. G., Platsoucas C. D., Rashed S., Wharton J. T., Edwards C. L., Freedman R. S. Tumor cytolysis by lymphocytes infiltrating ovarian malignant ascites. Cancer Res. 1991 Aug 15;51(16):4257–4265. [PubMed] [Google Scholar]
  20. Ioannides C. G., Rashed S., Fisk B., Fan D., Itoh K., Freedman R. S. Lymphocytes infiltrating ovarian malignant ascites: modulation of IL-2-induced proliferation by IL-4 and of selective increase in CD8+ T cells by TNF-alpha. Lymphokine Cytokine Res. 1991 Aug;10(4):307–315. [PubMed] [Google Scholar]
  21. Kawakami Y., Rosenberg S. A., Lotze M. T. Interleukin 4 promotes the growth of tumor-infiltrating lymphocytes cytotoxic for human autologous melanoma. J Exp Med. 1988 Dec 1;168(6):2183–2191. doi: 10.1084/jem.168.6.2183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Laszlo J., Goldstein D., Gockerman J., Hood L., Huang A. T., Triozzi P., Sedwick W. D., Koren H., Ellinwood E. H., Tso C. Y. Phase I studies of recombinant interferon-gamma. J Biol Response Mod. 1990 Apr;9(2):185–193. [PubMed] [Google Scholar]
  23. Lienard D., Ewalenko P., Delmotte J. J., Renard N., Lejeune F. J. High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol. 1992 Jan;10(1):52–60. doi: 10.1200/JCO.1992.10.1.52. [DOI] [PubMed] [Google Scholar]
  24. Mizel S. B. Interleukin 1 and T cell activation. Immunol Rev. 1982;63:51–72. doi: 10.1111/j.1600-065x.1982.tb00411.x. [DOI] [PubMed] [Google Scholar]
  25. Osband M. E., Lavin P. T., Babayan R. K., Graham S., Lamm D. L., Parker B., Sawczuk I., Ross S., Krane R. J. Effect of autolymphocyte therapy on survival and quality of life in patients with metastatic renal-cell carcinoma. Lancet. 1990 Apr 28;335(8696):994–998. doi: 10.1016/0140-6736(90)91064-h. [DOI] [PubMed] [Google Scholar]
  26. Papamichail M., Baxevanis C. N. Gamma-interferon enhances the cytotoxic activity of interleukin-2-induced peripheral blood lymphocyte (LAK) cells, tumor infiltrating lymphocytes (TIL), and effusion associated lymphocytes. J Chemother. 1992 Dec;4(6):387–393. doi: 10.1080/1120009x.1992.11739197. [DOI] [PubMed] [Google Scholar]
  27. Plebanski M., Elson C. J., Billington W. D. Dependency on interleukin-1 of primary human in vitro T cell responses to soluble antigens. Eur J Immunol. 1992 Sep;22(9):2353–2358. doi: 10.1002/eji.1830220926. [DOI] [PubMed] [Google Scholar]
  28. Rosenberg S. A., Packard B. S., Aebersold P. M., Solomon D., Topalian S. L., Toy S. T., Simon P., Lotze M. T., Yang J. C., Seipp C. A. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988 Dec 22;319(25):1676–1680. doi: 10.1056/NEJM198812223192527. [DOI] [PubMed] [Google Scholar]
  29. Shimizu Y., Iwatsuki S., Herberman R. B., Whiteside T. L. Effects of cytokines on in vitro growth of tumor-infiltrating lymphocytes obtained from human primary and metastatic liver tumors. Cancer Immunol Immunother. 1991;32(5):280–288. doi: 10.1007/BF01789045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Siegel J. P. Effects of interferon-gamma on the activation of human T lymphocytes. Cell Immunol. 1988 Feb;111(2):461–472. doi: 10.1016/0008-8749(88)90109-8. [DOI] [PubMed] [Google Scholar]
  31. Stötter H., Wiebke E. A., Tomita S., Belldegrun A., Topalian S., Rosenberg S. A., Lotze M. T. Cytokines alter target cell susceptibility to lysis. II. Evaluation of tumor infiltrating lymphocytes. J Immunol. 1989 Mar 1;142(5):1767–1773. [PubMed] [Google Scholar]
  32. Uhl J., Newton R. C., Giri J. G., Sandlin G., Horuk R. Identification of IL-1 receptors on human monocytes. J Immunol. 1989 Mar 1;142(5):1576–1581. [PubMed] [Google Scholar]
  33. Vaccarello L., Wang Y. L., Whiteside T. L. Sustained outgrowth of autotumor-reactive T lymphocytes from human ovarian carcinomas in the presence of tumor necrosis factor alpha and interleukin 2. Hum Immunol. 1990 Jun;28(2):216–227. doi: 10.1016/0198-8859(90)90022-h. [DOI] [PubMed] [Google Scholar]

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