Se. Hunter et al., IMMUNOREGULATION BY INTERLEUKIN-12 IN MB49.1 TUMOR-BEARING MICE - CELLULAR AND CYTOKINE-MEDIATED EFFECTOR MECHANISMS, European Journal of Immunology, 27(12), 1997, pp. 3438-3446
Administration of recombinant murine interleukin (rmIL)-12 to MB49.1 t
umor-bearing mice results in dose-dependent regression of the primary
tumor and the generation of protective antitumor immunity in the major
ity of animals. rmIL-12 administration is associated with a marked inc
rease in lymph node cellularity that is predominantly due to the expan
sion of B220(+) B cells as well as CD8(+) T cells. Stimulation of lymp
h node cells from mIL-12-treated, but not control tumor-bearing mice,
with MB49.1 tumor cells in vitro was shown to enhance the secretion of
interferon (IFN)-gamma. The magnitude of this in vitro response was d
ependent on the dose of rmIL-12 administered in vivo and mirrored the
change in circulating serum IFN-gamma. Furthermore, at the height of t
he in vitro response to tumor stimulation, the addition of a neutraliz
ing antibody to murine IL-12 suppressed IFN-gamma production, indicati
ng a role for endogenous IL-12 in this antigen-specific cytokine respo
nse. Although studies in SCID mice confirmed that an appropriate T cel
l response was required for rmIL-12-mediated antitumor activity, in im
munocompetent animals early tumor regression was not accompanied by ce
llular infiltration of the tumor. In contrast, a profound increase in
tumor-associated inducible nitric oxide synthase (iNOS) was observed i
n mice receiving rmIL-12 which preceded T cell infiltration of the tum
or 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 t
he host to mount a subsequent T cell response against the tumor.