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Tumor Cell Clone Expressing the Membrane-bound Form of IL-12p35 Subunit Stimulates Antitumor Immune Responses Dominated by CD8＋ T Cells

박상민|김영상|임호영|도선아
대한면역학회 (The Korean Association of Immunologists)|2013.04|Immune Network|제13권 제2호|pp. 63-69|DOI 10.4110

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키워드

Interleukin-12Membrane-bound formp35 subunitp40 subunitMethA fibrosarcoma

초록

IL-12 is a secretory heterodimeric cytokine composed of p35and p40 subunits. IL-12 p35 and p40 subunits are sometimes produced as monomers or homodimers. IL-12 is also produced as a membrane-bound form in some cases. In this study, we hypothesized that the membrane-bound form of IL-12 subunits may function as a costimulatory signal for selective activation of TAA-specific CTL through direct priming without involving antigen presenting cells and helper T cells. MethA fibrosarcoma cells were transfected with expression vectors of membrane-bound form of IL-12p35 (mbIL-12p35)or IL-12p40 subunit (mbIL-12p40) and were selected under G418-containing medium. The tumor cell clones were analyzed for the expression of mbIL-12p35 or p40 subunit and for their stimulatory effects on macrophages. The responsible T-cell subpopulation for antitumor activity of mbIL-12p35 expressing tumor clone was also analyzed in T cell subset-depleted mice. Expression of transfected membranebound form of IL-12 subunits was stable during more than 3months of in vitro culture, and the chimeric molecules were not released into culture supernatants. Neither the mbIL-12p35-expressing tumor clones nor mbIL-12p40-expressing tumor clones activated macrophages to secrete TNF-α. Growth of mbIL-12p35-expressing tumor clones was more accelerated in the CD8＋ T cell-depleted mice than in CD4＋T cell-depleted or normal mice. These results suggest that CD8＋ T cells could be responsible for the rejection of mbIL-12p35-expressing tumor clone, which may bypass activation of antigen presenting cells and CD4＋ helper T cells.

Abstract

IL-12 is a secretory heterodimeric cytokine composed of p35and p40 subunits. IL-12 p35 and p40 subunits are sometimes produced as monomers or homodimers. IL-12 is also produced as a membrane-bound form in some cases. In this study, we hypothesized that the membrane-bound form of IL-12 subunits may function as a costimulatory signal for selective activation of TAA-specific CTL through direct priming without involving antigen presenting cells and helper T cells. MethA fibrosarcoma cells were transfected with expression vectors of membrane-bound form of IL-12p35 (mbIL-12p35)or IL-12p40 subunit (mbIL-12p40) and were selected under G418-containing medium. The tumor cell clones were analyzed for the expression of mbIL-12p35 or p40 subunit and for their stimulatory effects on macrophages. The responsible T-cell subpopulation for antitumor activity of mbIL-12p35 expressing tumor clone was also analyzed in T cell subset-depleted mice. Expression of transfected membranebound form of IL-12 subunits was stable during more than 3months of in vitro culture, and the chimeric molecules were not released into culture supernatants. Neither the mbIL-12p35-expressing tumor clones nor mbIL-12p40-expressing tumor clones activated macrophages to secrete TNF-α. Growth of mbIL-12p35-expressing tumor clones was more accelerated in the CD8＋ T cell-depleted mice than in CD4＋T cell-depleted or normal mice. These results suggest that CD8＋ T cells could be responsible for the rejection of mbIL-12p35-expressing tumor clone, which may bypass activation of antigen presenting cells and CD4＋ helper T cells.

참고문헌 (42)

  1. Kobayashi, M., "Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes", J. Exp. Med, 170, pp.827~845 (1989)
  2. Gately, M. K., "Synergy between recombinant interleukin 2 (rIL 2) and IL 2-depleted lymphokine-containing supernatants in facilitating allogeneic human cytolytic T lymphocyte responses in vitro", J. Immunol, 136, pp.1274~1282 (1986)
  3. Stern, A. S., "Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells", Proc. Natl. Acad. Sci. U. S. A, 87, pp.6808~6812 (1990)
  4. Hsieh, C. S., "Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages", Science, 260, pp.547~549 (1993)
  5. ) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells, "J. Exp. Med", 1993, 1199~1204
  6. Gately, M. K., "Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor)", J. Immunol, 147, pp.874~882 (1991)
  7. Trinchieri, G., "Interleukin-12: a cytokine at the interface of inflammation and immunity", Adv. Immunol, 70, pp.83~243 (1998)
  8. Weiss, J. M., "Immunotherapy of cancer by IL-12-based cytokine combinations", Expert. Opin. Biol. Ther, 7, pp.1705~1721 (2007)
  9. D'Andrea, A, "Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells", J. Exp. Med, 176, pp.1387~1398
  10. Gillessen, S., "Mouse interleukin-12 (IL-12) p40 homodimer: a potent IL-12 antagonist", Eur. J. Immunol, 25, pp.200~206 (1995)
  11. Heinzel, F. P., "In vivo production and function of IL-12 p40 homodimers", J. Immunol, 158, pp.4381~4388 (1997)
  12. Ling, P., "Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity", J. Immunol, 154, pp.116~127 (1995)
  13. Jana, M., "Induction of tumor necrosis factor-alpha (TNF-alpha) by interleukin-12 p40 monomer and homodimer in microglia and macrophages", J. Neurochem, 86, pp.519~528 (2003)
  14. Jana, M., "IL-12 p40 homodimer, but not IL-12 p70, induces the expression of IL-16 in microglia and macrophages", Mol. Immunol, 46, pp.773~783 (2009)
  15. Cooper, A. M, "IL-12p40: an inherently agonistic cytokine", Trends. Immunol, 28, pp.33~38 (2007)
  16. Khader, S. A., "Interleukin 12p40 is required for dendritic cell migration and T cell priming after Mycobacterium tuberculosis infection", J. Exp. Med, 203, pp.1805~1815 (2006)
  17. Fan, X., "The proinflammatory cytokine interleukin-12 occurs as a cell membrane-bound form on macrophages", Biochem. Biophys. Res. Commun, 225, pp.1063~1067 (1996)
  18. Wolf, S. F., "Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells", J. Immunol, 146, pp.3074~3081 (1991)
  19. Brunda, M. J., "Antitumor and antimetastatic activity of interleukin 12 against murine tumors", J. Exp. Med, 178, pp.1223~1230 (1993)
  20. Nastala, C. L., "Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production", J. Immunol, 153, pp.1697~1706 (1994)
  21. Atkins, M. B., "Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies", Clin. Cancer Res, 3, pp.409~417 (1997)
  22. Car, B. D., "The toxicology of interleukin-12: a review", Toxicol. Pathol, 27, pp.58~63 (1999)
  23. Leonard, J. P., "Effects of single-dose interleukin- 12 exposure on interleukin-12-associated toxicity and interferon-gamma production", Blood, 90, pp.2541~2548 (1997)
  24. 김영상, "Tumor Therapy Applying Membrane-bound Form of Cytokines", Immune Network, 9(5), pp.158~168 (2009), 대한면역학회
  25. Li, Q., "Mechanism of action differences in the antitumor effects of transmembrane and secretory tumor necrosis factor-alpha in vitro and in vivo", Cancer Immunol. Immunother, 55, pp.1470~1479 (2006)
  26. Rieger, R., "Chimeric form of tumor necrosis factor-alpha has enhanced surface expression and antitumor activity", Cancer Gene Ther, 16, pp.53~64 (2009)
  27. el-Shami, K. M., "Induction of antitumor immunity with modified autologous cells expressing membrane-bound murine cytokines", J. Interferon. Cytokine. Res, 19, pp.1391~1401 (1999)
  28. Soo Hoo, W., "Tumor cell surface expression of granulocyte-macrophage colony-stimulating factor elicits antitumor immunity and protects from tumor challenge in the P815 mouse mastocytoma tumor model", J. Immunol, 162, pp.7343~7349 (1999)
  29. Yei, S., "Novel membrane-bound GM-CSF vaccines for the treatment of cancer: generation and evaluation of mbGM-CSF mouse B16F10 melanoma cell vaccine", Gene Ther, 9, pp.1302~1311 (2002)
  30. 장미라, "Antitumor immunity induced by tumor cells engineered to express a membrane-bound form of IL-2", Experimental and Molecular Medicine, 37(3), pp.240~249 (2005), 생화학분자생물학회
  31. 최진화, "Anti-tumor Immunity Induced by Tumor Cells Expressing a Membrane-bound Form of IL-2 and SDF-1", Animal Cells and Systems, 12(4), pp.193~201 (2008), 한국통합생물학회
  32. Ji, J., "Glycoinositol phospholipid-anchored interleukin 2 but not secreted interleukin 2 inhibits melanoma tumor growth in mice", Mol. Cancer Ther, 1, pp.1019~1024 (2002)
  33. Ji, J., "Synergistic anti-tumor effect of glycosylphosphatidylinositol- anchored IL-2 and IL-12", J. Gene Med, 6, pp.777~785 (2004)
  34. SONN, CHUNG HEE, "MethA Fibrosarcoma Cells Expressing Membrane-Bound Forms of IL-2 Enhance Antitumor Immunity", Journal of Microbiology and Biotechnology, 16(12), pp.1919~1927 (2006), 한국미생물·생명공학회
  35. Chakrabarti, R., "Plasmids encoding membrane-bound IL-4 or IL-12 strongly costimulate DNA vaccination against carcinoembryonic antigen (CEA)", Vaccine, 22, pp.1199~1205 (2004)
  36. Kim, Y. S., "Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity", Gene Ther, 7, pp.837~843 (2000)
  37. Cimino, A. M., "Cancer vaccine development: protein transfer of membrane- anchored cytokines and immunostimulatory molecules", Immunol. Res, 29, pp.231~240 (2004)
  38. Lim, H. Y., "Antitumor effects of a tumor cell vaccine expressing a membrane- bound form of the IL-12 p35 subunit", Cancer Biol. Ther, 10, pp.336~343 (2010)
  39. 백소영, "Dendritic Cell (DC) Vaccine in Mouse Lung Cancer Minimal Residual Model; Comparison of Monocyte-derived DC vs. Hematopoietic Stem Cell Derived-DC", Immune Network, 12(6), pp.269~276 (2012), 대한면역학회
  40. Cohen, J, "IL-12 deaths: explanation and a puzzle", Science, 270, pp.908~ (1995)
  41. Okada, Y., "Optimization of antitumor efficacy and safety of in vivo cytokine gene therapy using RGD fiber-mutant adenovirus vector for preexisting murine melanoma", Biochim. Biophys. Acta, 1670, pp.172~180 (2004)
  42. Sun, Y., "Vaccination with IL-12 gene-modified autologous melanoma cells: preclinical results and a first clinical phase I study", Gene Ther, 5, pp.481~490 (1998)

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