Although interleukin-2 (IL-2) based immunotherapy regimens are intended to generate lymphokine-activated killer (LAK) cells, macrophages and also be activated by this lymphokine. Activated macrophages can produce monokines such as tumor necrosis factor (TNF), interleukin-1 and inflammatory mediators that include arachidonate metabolites. The overall contribution on IL- 2 activated macrophages to host antitumor immunity is not known. The overall aim of this study is to define possible toxicities and benefits of IL-2 macrophage activation. Direct IL-2 activation of tumor-associated macrophages (TAMs) could enhance their tumoricidal activity, recruit new effector cells or augment LAK activity. Alternatively, excessive production of monokines and metabolites by activated circulating monocytes and tissue macrophages could be responsible for many of the toxic and dose-limiting side-effects of systemic IL-2 administration if systemic macrophage activation adversely impacts on IL-2 based immunotherapy regimens, efforts to selectively inhibit macrophage function with pharmacological agents such as lipoxygenase, cycloxygenase or calcium channel inhibitors should greatly improve their therapeutic index.
