DIRECT KILLING OF INTERLEUKIN-2-TRANSFECTED TUMOR-CELLS BY HUMAN NEUTROPHILS

We have previously established that human polymorphonuclear cells (PMN ) express IL-2R beta- and gamma-chains and that addition of IL-2 maint ains the viability of PMN by preventing these cells from undergoing pr ogrammed cell death. The purpose of this study was to examine whether IL-2-releasing tumor cells are capable of stimulating PMN tumoricidal activity. We therefore investigated the ability of PMN to kill IL-2-tr ansfected tumor cells using normal human PMN directed against the muri ne mammary adenocarcinoma TS/A engineered to release high amounts of m urine IL-2 (3,600 U, B6) compared with TS/A parental cells and TS/A tu mor cells transfected with the neomycin-resistance (NEO) gene only. Th e potency of PMN as IL-2-induced killer cells was indicated by the low number of cells required for killing (effector cell:target cell ratio 10:1) and the degree of tumor cell lysis (68 +/- 10%). Evidence for t he role of IL-2 as a mediator of tumor cytotoxicity by PMN was substan tiated by inhibition of tumor killing with anti-IL-2 and anti-IL-2R be ta monoclonal antibodies (MAbs). Furthermore, in vivo depletion of mat ure granulocytes using MAb RB6-8C5 resulted in Bb adenocarcinoma growt h, thereby confirming a direct role for IL-2-activated PMN in tumor cy tolysis. Lastly, we suggest that one possible mechanism involved in IL -2-induced PMN cytotoxicity against the Bb clone occurs via the nitric oxide pathway, which could be inhibited upon addition of the arginine analog, N-G-monomethyl-L-arginine. (C) 1996 Wiley-Liss, Inc.