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Characterization of tumor-necrosis-factor-gene-transduced tumor-infiltrating lymphocytes from ascitic fluid of cancer patients: analysis of cytolytic activity, growth rate, adhesion molecule expression and cytokine production

  • Original Article
  • Tumor Necrosis Factor Gene, Tumor-Infiltrating Lymphocytes, Gene Transduction, Mechanisms
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

We characterized tumor-infiltrating lymphocytes (TIL) from ascites of patients with ovarian or pancreatic cancer in which the human tumor necrosis factor (TNF) gene was successfully transduced with retrovirus vector. The TNF-gene-transduced TIL (TNF-TIL) from these patients showed a higher level of TNF production and higher cytotoxic activity against K562 and Daudi cells than did neomycin-phosphotransferase-gene-transduced TIL (neo-TIL). Of these TIL preparations, only that from pancreatic cancer was further characterized since it was collected in a relatively large amount. In spite of the fact that the autologous tumor cells showed resistance to soluble TNF, the TNF-TIL clearly demonstrated enhanced cytotoxicity against them as compared with neo-TIL. The enhanced cytotoxicity was ascribed to autocrine effects of secreted TNF on TIL, which included augmentation of adhesion molecule (CD2 and CD11a) and interleukin-2 receptor expression, and elevation of production of interferon γ, lymphotoxin and granulocyte/macrophage-colonystimulating factor and its paracrine effect on target cells to facilitate them to be more susceptible to TIL.

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References

  1. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA (1982) Lymphokine-activated killer cell phenomenon. J Exp Med 155: 1823

    PubMed  Google Scholar 

  2. Rosenberg SA, Spiess P, Lafreniere RA (1986) New approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233: 1318

    PubMed  Google Scholar 

  3. Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE (1987) A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316: 889

    PubMed  Google Scholar 

  4. Fisher RI, Coltman CA Jr, Doroshow JH, Rayner AA, Hawkins MJ, Mier JW, Wiernik P, McMannis JD, Weiss GR, Margolin KA, Gemlo BT, Hoth DF, Parkinson DR, Paietta E (1988) Metastatic renal cancer treated with interleukin-2 and lymphokine-activated killer cells. A phase I clinical trial. Ann Intern Med 108: 518

    PubMed  Google Scholar 

  5. Koretz MJ, Lowson DH, York RM, Graham SD, Murray DR, Gillespie TM, Levitt D, Sell KM (1991) Randomized study of interleukin-2 (IL-2) alone vs IL-2 plus lymphokine-activated killer cells for treatment of melanoma and renal cell cancer. Arch Surg 126: 898

    PubMed  Google Scholar 

  6. Boldt DH, Mills BJ, Gemlo BT, Holden H, Mier J, Paietta E, McMannis JD, Escobedo LV, Sniecinski I, Rayner AA, Hawkins MJ, Atkins MB, Ciobanu N, Ellis TM (1988) Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans. Cancer Res 48: 4409

    PubMed  Google Scholar 

  7. Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA, Simpson C, Carter C, Bock S, Schwartzentruber D, Wei JP, White DE (1988) Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. N Engl J Med 319: 1676

    PubMed  Google Scholar 

  8. Kradin RL, Kurnick JT, Lazarus DS, Preffer II, Dubinett SM, Pinto CE, Gifford J, Davidson E, Grove B, Callahan RJ, Strauss HW (1989) Tumour-infiltrating lymphocytes and interleukin-2 in treatment of advanced cancer. Lancet 18: 577

    Google Scholar 

  9. Bukowski RM, Sharfman W, Murthy S, Rayaman P, Tubbs R, Alexander J, Budd GT, Sergi JS, Bauer L, Gibson V, Stanley J, Boyett J, Pontes E, Finke J (1991) Clinical results and characterization of tumor-infiltrating lymphocytes with or without recombinant interleukin 2 in human metastatic renal cell carcinoma. Cancer Res 51: 4199

    PubMed  Google Scholar 

  10. Aebersold P, Hyatt C, Johnson S, Hines K, Korcak L, Sanders M, Lótze M, Topalian S, Yang J, Rosenberg SA (1991) Lysis of autologous melanoma cells by tumor-infiltrating lymphocytes: association with clinical response. J Natl Cancer Inst 83: 93211

    Google Scholar 

  11. Watanabe N, Niitsu Y, Neda H, Sone H, Yamauchi N, Umetsu T, Urushizaki I (1985) Antitumor effect of tumor necrosis factor against various primarily cultured human cancer cells. Jpn J Cancer Res 76: 1115

    PubMed  Google Scholar 

  12. Watanabe N, Niitsu Y, Umeno T, Kuriyama H, Neda H, Yamauchi N, Maeda M, Urushizaki I (1988) Toxic effect of tumor necrosis factor on tumor vasculature in mice. Cancer Res 48: 2179

    PubMed  Google Scholar 

  13. Ostensen ME, Thiele DL, Lipski PE (1987) Tumor necrosis factor-α enhances cytolytic activity of human natural killer cells. J Immunol 138: 4185

    PubMed  Google Scholar 

  14. Owen-Schaub LB, Gutterman JU, Grimm EA (1988) Synergy of tumor necrosis factor and interleukin 2 in the activation of human cytotoxic lymphocytes: effect of tumor necrosis factor alpha and interleukin 2 in the generation of human lymphokine-activated killer cell cytotoxicity. Cancer Res 48: 788

    PubMed  Google Scholar 

  15. Itoh Y, Kohgo Y, Watanabe N, Kanisawa Y, Sakamaki S, Takahashi M, Hirayama Y, Ono H, Himeno T, Niitsu Y (1991) Human tumor-infiltrating lymphocytes transfected with tumor necrosis factor gene could augment cytotoxicity to autologous tumor cells. Jpn J Cancer Res 82: 1203

    PubMed  Google Scholar 

  16. Rosenberg SA (1991) Immunotherapy and gene therapy of cancer. Cancer Res 51: 5074

    Google Scholar 

  17. Himeno T, Watanabe N, Yamauchi N, Maeda M, Tsuji Y, Okamoto T, Neda H, Niitsu Y (1990) Expression of endogenous tumor necrosis factor as a protective protein against the cytotoxicity of exogenous tumor necrosis factor. Cancer Res 50: 4941

    PubMed  Google Scholar 

  18. Korman AJ, Frantz JD, Strominger JL, Mulligan RC (1987) Expression of human class I major histocompatibility complex antigens using retrovirus vectors. Proc Natl Acad Sci USA 84: 2150

    PubMed  Google Scholar 

  19. Bender MA, Palmer TD, Gelinas RE, Miller AD (1987) Evidence that the packaging signal of moloney murine leukemia virus extends into the gag region. J Virol 61: 1639

    PubMed  Google Scholar 

  20. Danos O, Mulligan RC (1988) Safe and efficient generation of recombinant retroviruses with amphotropic and ecotropic host ranges. Proc Natl Acad Sci USA 85: 6460

    PubMed  Google Scholar 

  21. Tsuji Y, Watanabe N, Okamoto T, Tsuji N, Sasaki H, Akiyama S, Yamauchi N, Niitsu Y (1992) Endogenous tumor necrosis factor functions as a resistant factor against hyperthermic cytotoxicity. Cancer Res 52: 6258

    PubMed  Google Scholar 

  22. Fujii S, Liu Y, Neda H, Itoh Y, Koshita Y, Takahashi M, Watanabe N, Kohgo Y, Niitsu Y (1994) Augmented systemic immunity in mice implanted with tumor necrosis factor-α gene-transduced Meth-A cells. Jpn J Cancer Res 85: 315

    PubMed  Google Scholar 

  23. Himeno T, Watanabe N, Yamauchi N, Maeda M, Okamoto T, Tsuji N, Tsuji Y, Akiyama S, Sasaki H, Niitsu Y (1992) Induction of synthesis of manganous superoxide dismutase in L-M (en TNF) cells carrying an inducible TNF gene. Int J Cancer 50: 458

    PubMed  Google Scholar 

  24. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65: 55

    PubMed  Google Scholar 

  25. Niitsu Y, Watanabe N, Umeno H, Sone H, Neda H, Yamauchi N, Maeda M, Urushizaki I (1988) Synergistic effects of recombinant human tumor necrosis factor and hyperthermia on in vitro cytotoxicity and artificial metastases. Cancer Res 48: 654

    PubMed  Google Scholar 

  26. Watanabe N, Niitsu Y, Umeno H, Sone H, Neda H, Yamauchi N, Maeda M, Urushizaki I (1988) Synergistic cytotoxic and antitumor effects of recombinant human tumor necrosis factor and hyperthermia. Cancer Res 48: 650

    PubMed  Google Scholar 

  27. Kono R, Vilcek J (eds) (1980) The clinical potential of interferons. University of Tokyo press, Tokyo, p 299

    Google Scholar 

  28. Yamazaki S, Onishi E, Enami K, Natori K, Kohase M, Sakamoto H, Tanouchi M, Hayashi H (1986) Proposal of standardized methods and reference for assaying recombinant human tumor necrosis factor. Jpn J Med Sci Biol 39: 105

    PubMed  Google Scholar 

  29. Gray PW (1984) Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumor necrosis activity. Nature 312: 721

    PubMed  Google Scholar 

  30. Springett GM, Moen RC, Anderson S, Blaese RM, Anderson WF (1989) Infection efficiency of T lymphocytes with amphotropic retroviral vectors is cell cycle dependent. J Virol 63: 3865

    PubMed  Google Scholar 

  31. Yang SC, Owen-Schaub LB, Roth JA, Grimm EA (1990) Characterization of OKT3-initiated lymphokine-activated effectors expanded with interleukin 2 and tumor necrosis factor alpha. Cancer Res 50: 3526

    PubMed  Google Scholar 

  32. Springer TA, Dustin ML, Kishimoto TK, Marlin SD (1987) The lymphocyte function-associated LFA-1, CD2, and LFA-3 molecules: cell adhesion receptors of the immune system. Annu Rev Immunol 5: 223

    PubMed  Google Scholar 

  33. Nakamura T, Takahashi K, Fukazawa T, Koyanagi M, Yokoyoma A, Kato H, Yagita H, Oumura K (1990) Relative contribution of CD2 and LFA-1 to murine T and natural killer cell functions. J Immunol 145: 3628

    PubMed  Google Scholar 

  34. Kato K, Tanabe T, Yagita H, Agatsuma T, Hojo H, Hashimoto Y (1991) Adhesion molecules on murine lymphokine-activated killer cells responsible for target cell killing a role of CD2. Jpn J Cancer Res 82: 1139

    PubMed  Google Scholar 

  35. Lanier LL, Chang C, Azuma M, Ruitenberg JJ, Hemperly JJ, Phillips JH (1991) Molecular and functional analysis of human natural killer cell-associated neural cell adhesion molecules (N-CAM/CD56). J Immunol 146: 4421

    PubMed  Google Scholar 

  36. Ellis TM, McKenzie RS, Simms PE, Helfrich BA, Fisher R (1989) Induction of human lymphokine-activated killer cells by IFN-alpha and IFN-gamma. J Immunol 143: 4282

    PubMed  Google Scholar 

  37. Johnson HM, Farrar WL (1983) The role of a gamma interferon-like lymphokine in the activation of T cell for expression of interleukin 2 receptors. Cell Immunol 75: 154

    PubMed  Google Scholar 

  38. Singh SM, Sone S, Inamura N, Ogura T (1989) Up-regulation by granulocyte-macrophage colony-stimulating factor (GM-CSF) of induction of lymphokine (IL-2)-activated killer (LAK) cells by human blood monocytes. Int J Cancer 44: 170

    PubMed  Google Scholar 

  39. Masucci G, Ragnhammer P, Wersall P, Mellsted H (1990) Granulocytemonocyte colony-stimulating-factor augments the interleukin-2-induced cytotoxic activity of human lymphocytes in the absence and presence of mouse or chimeric monoclonal antibodies (mAb-17-1A). Cancer Immunol Immunother 31: 231

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, 060, Sapporo, Japan

    Yoshinori Itoh, Yoshikazu Koshita, Minoru Takahashi, Naoki Watanabe, Yutaka Kohgo & Yoshiro Niitsu

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  1. Yoshinori Itoh
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  2. Yoshikazu Koshita
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  3. Minoru Takahashi
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  4. Naoki Watanabe
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  5. Yutaka Kohgo
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  6. Yoshiro Niitsu
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Itoh, Y., Koshita, Y., Takahashi, M. et al. Characterization of tumor-necrosis-factor-gene-transduced tumor-infiltrating lymphocytes from ascitic fluid of cancer patients: analysis of cytolytic activity, growth rate, adhesion molecule expression and cytokine production. Cancer Immunol Immunother 40, 95–102 (1995). https://doi.org/10.1007/BF01520290

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  • DOI: https://doi.org/10.1007/BF01520290

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