Complete regression of established spontaneous mammary carcinoma and the therapeutic prevention of genetically programmed neoplastic transition by IL-12/pulse IL-2: Induction of local T cell infiltration, Fas/Fas ligand geneexpression, and mammary epithelial apoptosis
Jm. Wigginton et al., Complete regression of established spontaneous mammary carcinoma and the therapeutic prevention of genetically programmed neoplastic transition by IL-12/pulse IL-2: Induction of local T cell infiltration, Fas/Fas ligand geneexpression, and mammary epithelial apoptosis, J IMMUNOL, 166(2), 2001, pp. 1156-1168
Using a novel transgenic mouse model of spontaneous mammary carcinoma, we s
how here that the IL-12/pulse IL-2 combination can induce rapid and complet
e regression of well-established autochthonous tumor in a setting where the
host immune system has been conditioned by the full dynamic process of neo
plastic progression and tumorigenesis. Further, this regimen inhibits neova
scularization of established mammary tumors, and does so in conjunction wit
h potent local induction of genes encoding the IFN-gamma- and TNF-alpha -in
ducible antiangiogenic chemokines IFN-inducible protein 10 and monokine ind
uced by IFN-gamma. In contrast to untreated juvenile C3(1)TAg mice in which
histologically normal mammary epithelium predictably undergoes progressive
hyperplasia, atypical changes, and ultimately transition to overt carcinom
a, the current studies also demonstrate a unique preventative therapeutic r
ole for IL-12/pulse IL-2. In juvenile mice, early administration of IL-12/p
ulse IL-2 markedly limits the expected genetically programmed neoplastic tr
ansition within the mammary epithelium and does so in conjunction with enha
ncement of constitutive Fas and pronounced induction of local Fas ligand ge
ne expression, T cell infiltration, and induction of apoptosis within the m
ammary epithelium. These events occur in the absence of a durable Ag-specif
ic memory response. Thus, this novel model system demonstrates that the pot
ent therapeutic activity of the IL-12/pulse IL-2 combination rapidly engage
s potent apoptotic and antiangiogenic mechanisms that remain active during
the delivery of IL-12/pulse IL-2. The results also demonstrate that these m
echanisms are active against established tumor as well as developing preneo
plastic lesions.