Immunoregulation by interleukin-12 in MB49.1 tumor-bearing mice: Cellular and cytokine-mediated effector mechanisms

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Abstract
Administration of recombinant murine interleukin (rmlL)-12 to MB49.1 tumor-bearing mice results in dose-dependent regression of the primary tumor and the generation of protective antitumor immunity in the majority of animals. rmlL-12 administration is associated with a marked increase in lymph node cellularity that is predominantly due to the expansion of B220+ B cells as well as CD8+ T cells. Stimulation of lymph node cells from rmlL-12-treated, but not control tumor-bearing mice, with MB49.1 tumor cells in vitro was shown to enhance the secretion of interferon (IFN)-γ. The magnitude of this in vitro response was dependent on the dose of rmlL-12 administered in vivo and mirrored the change in circulating serum IFN-γ. Furthermore, at the height of the in vitro response to tumor stimulation, the addition of a neutralizing antibody to murine IL-12 suppressed IFN-γ production, indicating a role for endogenous IL-12 in this antigen-specific cytokine response. Although studies in SCID mice confirmed that an appropriate T cell response was required for rmlL-12-mediated antitumor activity, in immunocompetent animals early tumor regression was not accompanied by cellular infiltration of the tumor. In contrast, a profound increase in tumor-associated inducible nitric oxide synthase (iNOS) was observed in mice receiving rmlL-12 which preceded T cell infiltration of the tumor which could be detected during the second week of IL-12 treatment. Direct tumor killing through the cytotoxic actions of NO via the iNOS pathway may serve as a way of generating tumor antigen which enables the host to mount a subsequent T cell response against the tumor.

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