Cancer Immunology, Immunotherapy

, Volume 35, Issue 1, pp 14–18 | Cite as

Tumor-derived cytokines induce bone marrow suppressor cells that mediate immunosuppression through transforming growth factor β

  • M. Rita I. Young
  • Mark A. Wright
  • Michael Coogan
  • Melvin E. Young
  • Jamila Bagash
Original articles

Summary

Normal bone marrow cells become immunosuppressive when cultured with supernatants of metastatic Lewis lung carcinoma (LLC-LN7) cells. The suppressorinducing activities in the LLC-LN7 supernatants are interleukin-3 and granulocyte/macrophage-colony-stimulating factor. In the present study, the mechanisms by which these induced suppressor cells (LLCsup-BM) mediate their immunosuppression were investigated. The suppression by LLCsup-BM of splenic concanavalin CA blastogenesis was not dependent on cell contact since immunosuppression occurred regardless of whether the LLCsup-BM were separated from the responder spleen cells by a permeable membrane or if the LLCsup-BM were cocultured with the spleen cells. Culture supernatants of LLCsup-BM also inhibited T cell blastogenesis, being more suppressive than were supernatants of control bone marrow cells, which had been precultured with medium. The suppression by the soluble inhibitors elaborated from the LLCsup-BM was not restricted to the inhibition of T cell function as the supernatants also inhibited the natural killer activity of normal spleen cells. Studies to determine the identity of the suppressive activity produced by the LLCsup-BM showed increased levels of transforming growth factor β (TGFβ) in their supernatants. Immunosuppressive bone marrow and spleen cells obtained from mice bearing metastatic LLC-LN7 tumors also secreted more TGFβ than did the cells obtained from normal mice. When anti-TGFβ antibodies were added to the LLCsup-BM supernatants, the suppressive activity was diminished. These results suggest that the LLCsup-BM mediate at least part of their immunosuppression through production of TGFβ.

Key words

Lewis lung carcinoma TGFβ Bone marrow Immunosuppressor 

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References

  1. 1.
    Awwad M, North RJ (1989) Cyclophosphamide-induced immunologically mediated regression of a cyclophosphamide-resistant murine tumor: a consequence of eliminating precursor L3T4+ suppressor T-cells. Cancer Res 49: 1649Google Scholar
  2. 2.
    Brooks B, Chapman K, Lawry J, Meager A, Rees RC (1990) Suppression of lymphokine-activated killer (LAK) cell induction mediated by interleukin-4 and transforming growth factor-β1. effect of addition of exogenous tumour necrosis factor-alpha and interferongamma, and measurement of their endogenous production. Clin Exp Immunol 82: 583Google Scholar
  3. 3.
    Chakraborty NG, Twardzik DR, Sivanandham M, Ergin MT, Hellstrom KE, Mukherji B (1990) Autologous melanoma-induced activation of regulatory T cells that suppress cytotoxic response. J Immunol 145: 2359Google Scholar
  4. 4.
    Clark DA, Falbo M, Rowley RB, Banwatt D, Stedronska-Clark J (1988) Active suppression of host-vs-graft reaction in pregnant mice: IX. Soluble suppressor activity obtained from allopregnant mouse decidua that blocks the cytolytic effector response to IL-2 is related to transforming growth factor-β. J Immunol 141: 3833Google Scholar
  5. 5.
    Cleveland MG, Lane RG, Klimpel GR (1988) Spontaneous IFN-beta production. A common feature of natural suppressor systems. J Immunol 141: 2043Google Scholar
  6. 6.
    Fu Y-X, Watson GA, Kasahara M, Lopez DM (1991) The role of tumor-derived cytokines on the immune system of mice bearing a mammary adenocarcinoma: I. Induction of regulatory macrophages in normal mice by the in vivo administration of rGM-CSF. J Immunol 146: 783Google Scholar
  7. 7.
    Geller RL, Smyth MJ, Strobl SL, Bach FH, Ruscetti FW, Longo DL, Ochoa AC (1991) Generation of lymphokine-activated killer activity in T cells. Possible regulatory circuits. J Immunol 146: 3280Google Scholar
  8. 8.
    Goey H, Keller JR, Back T, Longo DL, Ruscetti FW, Wiltrout RH (1989) Inhibition of early murine hemopoietic progenitor cell proliferation after in vivo locoregional administration of transforming growth factor-β1. J Immunol 143: 877Google Scholar
  9. 9.
    Hooper WC (1991) The role of transforming growth factor-beta in hematopoiesis. A review. Leuk Res 15: 179Google Scholar
  10. 10.
    Jacobsen SE, Ruscetti FW, Dubois CM, Lee J, Boone TC, Keller JR (1991) Transforming growth factor-beta trans-modulates the expression of colony stimulating factor receptors on murine hematopoietic progenitor cell lines. Blood 77: 1706Google Scholar
  11. 11.
    Karpus WJ, Swanborg RH (1991) CD4+ suppressor cells inhibit the function of effector cells of experimental autoimmune encephalomyelitis through a mechanism involving transforming growth factor-β. J Immunol 146: 1163Google Scholar
  12. 12.
    Lotem J, Sachs L (1990) Selective regulation of the activity of different hematopoietic regulatory proteins by transforming growth factor beta 1 in normal and leukemic myeloid cells. Blood 76: 1315Google Scholar
  13. 13.
    Lotz M, Kekow J, Carson DA (1990) Transforming growth factor-β and cellular immune responses in synovial fluids. J Immunol 144: 4189Google Scholar
  14. 14.
    Maier T, Holda JH, Claman HN (1989) Murine natural suppressor cells in the newborn, in bone marrow, and after cyclophosphamide. Genetic variations and dependence on IFN-gamma. J Immunol 143: 491Google Scholar
  15. 15.
    Markovic SN, Murasko DM (1991) Role of natural killer and T-cells in interferon induced inhibition of spontaneous metastases of the B16-F10L murine melanoma. Cancer Res 51: 1124Google Scholar
  16. 16.
    Mortari F, Singhal SK (1988) Production of human bone marrowderived suppressor factor. Effect on antibody synthesis and lectin-activated cell proliferation. J Immunol 141: 3037Google Scholar
  17. 17.
    Nelson BJ, Ralph P, Green SJ, Nacy CA (1991) Differential susceptibility of activated macrophage cytotoxic effector reactions to the suppressive effects of transforming growth factor-β1. J Immunol 146: 1849Google Scholar
  18. 18.
    Sakata T, Iwagami S, Tsuruta Y, Teraoka H, Hojo K, Suzuki S, Sato K, Suzuki R (1990) The role of lipocortin I in macrophage-mediated immunosuppression in tumor-bearing mice. J Immunol 145: 387Google Scholar
  19. 19.
    Sing GK, Keller JR, Ellingsworth LR, Ruscetti FW (1989) Transforming growth factor-betal enhances the suppression of human hematopoiesis by tumor necrosis factor-alpha or recombinant interferon-alpha. J Cell Biochem 39: 107Google Scholar
  20. 20.
    Smyth MJ, Strobl SL, Young HA, Ortaldo JR, Ochoa AC (1991) Regulation of lymphokine-activated killer activity and pore-forming protein gene expression in human peripheral blood CD8+ T lymphocytes. Inhibition by transforming growth factor-beta. J Immunol 146: 3289Google Scholar
  21. 21.
    Tada T, Ohzeki S, Utsumi K, Takiuchi H, Maramatsu M, Li X-F, Shimizu J, Fujiwara H, Hamaoka T (1991) Transforming growth factor-β-induced inhibition of T cell function. Susceptibility difference in T cells of various phenotypes and functions and its relevance to immunosuppression in the tumor-bearing state. J Immunol 146: 1077Google Scholar
  22. 22.
    Tsuchiya Y, Igarashi M, Suzuki R, Kumagai K (1988) Production of colony-stimulating factor by tumor cells and the factor-mediated induction of suppressor cells. J Immunol 141: 699Google Scholar
  23. 23.
    Weingust RW, McCain GA, Singhal SK (1989) Regulation of autoimmunity in normal and rheumatoid individuals by bone marrowderived natural suppressor cells and their suppressor factor: BDSF. Cell Immunol 122: 154Google Scholar
  24. 24.
    Young MR, Wheeler E, Newby M (1986) Macrophage-mediated suppression of natural killer cell activity in mice bearing Lewis lung carcinoma. J Natl Cancer Inst 76: 745Google Scholar
  25. 25.
    Young MR, Newby M, Wepsic HT (1987) Hematopoiesis and suppressor bone marrow cells in mice bearing large metastatic Lewis lung carcinoma tumors. Cancer Res 47: 100Google Scholar
  26. 26.
    Young MR, Aquino S, Young ME (1989) Differential induction of hematopoiesis and immune suppressor cells in the bone marrow versus in the spleen by Lewis lung carcinoma variants. J Leuk Biol 452: 262Google Scholar
  27. 27.
    Young MRI, Young ME, Wright MA (1990) Stimulation of immune suppressive bone marrow cells by colony stimulating factors. Exp Hematol 18: 806Google Scholar
  28. 28.
    Young MRI, Young ME, Wright MA (1990) Myelopoiesis-associated suppressor cell activity in mice with Lewis lung carcinoma tumors: interferon-γ plus tumor necrosis factor-α synergistically reduce suppressor cell activity. Int J Cancer 46: 245Google Scholar
  29. 29.
    Young MRI, Wright MA, Young ME (1991) Antibodies to colonystimulating factors block Lewis lung carcinoma cell-stimulation of immune suppressive bone marrow cells. Cancer Immunol Immunother 33: 146Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • M. Rita I. Young
    • 1
    • 2
  • Mark A. Wright
    • 1
    • 2
  • Michael Coogan
    • 1
    • 2
  • Melvin E. Young
    • 1
    • 2
  • Jamila Bagash
    • 1
    • 2
  1. 1.Department of Research ServicesHines V. A. HospitalHinesUSA
  2. 2.Department of PathologyLoyola University Stritch School of MedicineMaywoodUSA

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