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Effects of lethal irradiation and cyclosporin A treatment on the growth and tumoricidal activity of a T cell clone potentially useful in cancer therapy

  • Original Article
  • MHC-Non-Restricted Tumoricidal Activity, Adoptive Transfer Therapy, Irradiated Killer Cells, Cyclosporin A Treatment, IL-2/IL-12 Activation
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The TALL-104 cell line, originally derived from a patient with T cell leukemia, can be maintained indefinitely in culture in the presence of interleukin-2 (IL-2) and is endowed with a highly potent major-histocompatibilitycomplex (MHC)-non-restricted tumoricidal activity both in vitro and in animal models. The present study analyzes in detail the short- and long-term effects of irradiation and cyclosporin A (CsA) treatment on the growth and tumoricidal function of this T cell clone as compared to polyclonal lymphokine-activated killer (LAK) cell preparations from healthy donors. DNA and RNA syntheses by both TALL-104 and LAK cells were irreversibly arrested a few hours after irradiation with 40 Gy. However, 4-h51Cr-release assays, performed on different days (day 1 to day 7) after irradiation, showed that the cytotoxic efficiency of TALL-104 cells against hematopoietic and solid tumor targets was only modestly reduced, whereas that of LAK cells was severely inhibited. Moreover, the cytotoxic responses to recombinant human IL-2 and IL-12, measured 18 h after irradiation and cytokine addition, were normal in the case of TALL-104 cells but were abolished in the case of LAK cells. Co-culture of IL-2-or IL-12-preactivated TALL-104 cells with a tumor target for 5 days in the absence of cytokines resulted in a lower efficiency of lysis, as compared to the non-irradiated effectors, especially if the initial stimulus was IL-12. These findings suggest the requirement of multiple cytokine stimulation for optimal expression of tumoricidal activity by lethally irradiated TALL-104 cells. CsA, while abrogating TALL-104 cell proliferation at the low dose of 0.5 μg/ml, inhibited their cytotoxic function marginally only at high doses (100 μg/ml). By contrast, CsA reduced dose-dependently the cytotoxicity of LAK cells starting at very low doses (0.5 μg/ml). CsA did not impair the ability of TALL-104 and LAK cells to produce interferon (IFN)γ, tumor necrosis factor (TNF) α, and granulocyte/macrophage-colony-stimulatory factor (GM-CSF) in response to IL-2, IL-12, or tumor targets. Irradiation reduced drastically IFNγ production by LAK, but not TALL-104 cells; release of TNFα and GM-CSF by either type of effector was inhibited by 10%–50%, depending on the stimulus. The high resistance of the TALL-104 cells' tumoricidal function to irradiation and immunosuppressive drugs renders this immortal T cell clone a potentially safe and effective reagent for new adoptive-transfer approaches to cancer in MHC-incompatible recipients.

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Authors and Affiliations

  1. The Wistar Institute, 3601 Spruce Street, 19104, Philadelphia, PA, USA

    Alessandra Cesano, Sophie Visonneau, Livia Cioé & Daniela Santoli

  2. Genetics Institue, 87 Cambridge Park Drive, Cambridge, Mass, USA

    Steven C. Clark

Authors
  1. Alessandra Cesano
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  2. Sophie Visonneau
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  3. Livia Cioé
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  4. Steven C. Clark
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  5. Daniela Santoli
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Cesano, A., Visonneau, S., Cioé, L. et al. Effects of lethal irradiation and cyclosporin A treatment on the growth and tumoricidal activity of a T cell clone potentially useful in cancer therapy. Cancer Immunol Immunother 40, 139–151 (1995). https://doi.org/10.1007/BF01517345

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  • DOI: https://doi.org/10.1007/BF01517345

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