AUGMENTATION BY TUMOR-NECROSIS-FACTOR-ALPHA OF THE SYSTEMIC THERAPEUTIC EFFECT OF LYMPHOKINE-ACTIVATED KILLER-CELLS IN ADOPTIVE IMMUNOTHERAPY OF MURINE TUMOR

The therapeutic effect of a combined modality of lymphokine-activated killer (LAK) cells and tumor necrosis factor alpha (TNF-alpha) on MBL-2 tumor in C57BL/6 mice was studied. Murine LAK cells induced from splenocytes by interleukin 2 (IL2) could lyse MBL-2 target cells in vitro, but no enhancement of the LAK activity was found by the treatment of LAK cells with TNFa in vitro. However, the treatment of MBL-2 with TNF-alpha enhanced the sensitivity to LAK cells. Moreover, administration of TNF-alpha to mice bearing solid MBL-2 tumor led to increased tumor vascular permeability within 1 h, and resulted in the enhanced accumulation of systemically transferred LAK cells in tumor tissue. Based on these results, we treated MBL-2-bearing mice with TNF-alpha then with LAK cells 1 h later. No therapeutic effect was observed when tumor-bearing mice were treated with TNF-alpha alone or LAK cells plus IL2. However, adoptive immunotherapy using LAK cells and TNF-alpha had therapeutic effects, i.e., growth inhibition of tumor nodules and prolongation of survival. These results indicated that appropriately timed pretreatment of tumor-bearing mice with TNF-alpha augmented the anti-tumor efficacy of LAK cells.