F. Pericle et al., DIRECT KILLING OF INTERLEUKIN-2-TRANSFECTED TUMOR-CELLS BY HUMAN NEUTROPHILS, International journal of cancer, 66(3), 1996, pp. 367-373
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.