Interleukin (IL)-12 activates a T-cell-dependent antitumor immune response that is able to eradicate established large
tumors in a number of immunogenic
tumor models. The effector mechanisms in these dramatic antitumor responses have not yet been identified. In this report, we show that the effector mechanism of IL-12-induced rejection of established MCA207
tumors is unique in that it is not dependent on
perforin, Fas/
Fas ligand, and
nitric oxide. Study of
cyclophosphamide plus
IL-12 (Cy +
IL-12)-induced rejection of
ascites Sa1
tumor demonstrates that macrophages are the predominant immune cell infiltration in the
ascites. These macrophages possess nonspecific tumoricidal activity in vivo as immune distinct MCA207
tumor cells inoculated i.p., but not s.c., in mice bearing regressing Sa1
ascites tumors after Cy +
IL-12 therapy are rejected. Furthermore, Cy + IL-12-treated Sa1
ascites cells or macrophages, but not spleen macrophages from the same mouse or inflammatory macrophages induced by thioglycollate, are able to suppress the development of immune-irrelevant s.c.
tumors in a Winn assay. These macrophages kill various
tumor cells in a contact-dependent manner in vitro, and the cytotoxicity is preserved after fixation with
paraformaldehyde. These results demonstrate that activated macrophages function as effector cells in an IL-12-induced, T-cell-dependent eradication of established
tumors through a novel contact-dependent,
paraformaldehyde fixation-resistant, apoptosis-inducing mechanism.