EFFECTS OF LETHAL IRRADIATION AND CYCLOSPORINE-A TREATMENT ON THE GROWTH AND TUMORICIDAL ACTIVITY OF A T-CELL CLONE POTENTIALLY USEFUL IN CANCER-THERAPY

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-histoc ompatibility complex (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) tr eatment on the growth and tumoricidal function of this T cell clone as compared to polyclonal lymphokine-activated killer (LAK) cell prepara tions from healthy donors. DNA and RNA syntheses by both TALL-104 and LAK cells were irreversibly arrested a few hours after irradiation wit h 40 Gy. However, 4-h Cr-51- release assays, performed on different da ys (day 1 to day 7) after irradiation, showed that the cytotoxic effic iency of TALL-104 cells against hematopoietic and solid tumor targets was only modestly reduced, whereas that of LAK cells was severely inhi bited. Moreover, the cytotoxic responses to recombinant human IL-2, an d IL-12, measured 18 h after irradiation and cytokine addition, were n ormal in the case of TALL-104 cells but were abolished in the case of LAK cells. Go-culture of IL-2- or IL-12-preactivated TALL-104 cells wi th a tumor target for 5 days in the absence of cytokines resulted in a lower efficiency of lysis, as compared to the non-irradiated effecter s, especially if the initial stimulus was IL-12. These findings sugges t the requirement of multiple cytokine stimulation for optimal express ion of tumoricidal activity by lethally irradiated TALL-104 cells. CsA , while abrogating TALL-104 cell proliferation at the low dose of 0.5 mu g/ml, inhibited their cytotoxic function marginally only at high do ses (100 mu g/ml). By contrast, CsA reduced dose-dependently the cytot oxicity of LAK cells starting at very low doses (0.5 mu g/ml). CsA did not impair the ability of TALL-104 and LAK cells to produce interfero n (IFN) gamma, tumor necrosis factor (TNF) alpha, and granulocyte/macr ophage-colony-stimulatory factor (GM-CSF) in response to IL-2, IL-12, or tumor targets. Irradiation reduced drastically IFN gamma production by LAK, but not TALL-104 cells; release of TNF alpha and GM-CSF by ei ther type of effector was inhibited by 10%-50%, depending on the stimu lus. The high resistance of the TALL-104 cells' tumoricidal function t o irradiation and immunosuppressive drugs renders this immortal T cell clone a potentially safe and effective reagent for new adoptive-trans fer approaches to cancer in MHC-incompatible recipients.