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*
Institute for Cancer Research and Treatment and Department of Genetics, Biology, and Biochemistry, University of Torino, Candiolo, Italy;
Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy;
Institute for Cancer Research and Treatment and Ordine del Mauriziano, Laboratory of Tumor Immunology, Candiolo, Italy; and
Immunotherapy and Gene Therapy Unit, Istituto Nazionaletumori, Milan, Italy
In vivo IL-12-dependent tumor inhibition rests on the ability of
IL-12 to activate a CD8-mediated cytotoxicity, inhibit angiogenesis,
and cause vascular injury. Although in vivo studies have shown that
such inhibition stems from complex interactions of immune cells and the
production of IFN-
and other downstream angiostatic chemokines, the
mechanisms involved are still poorly defined. Here we show that IL-12
activates an anti-angiogenic program in Con A-activated mouse
spleen cells (activated spc) or human PBMC (activated PBMC). The
soluble factors they release in its presence arrest the cycle of
endothelial cells (EC), inhibit in vitro angiogenesis, negatively
modulate the production of matrix metalloproteinase-9, and the ability
of EC to adhere to vitronectin and up-regulate ICAM-1 and VCAM-1
expression. These effects do not require direct cell-cell contact, yet
result from continuous interaction between activated lymphoid cells and
EC. We used neutralizing Abs to show that the IFN-inducible protein-10
and monokine-induced by IFN- chemokines are pivotal in inducing
these effects. Experiments with nu/nu mice, nonobese
diabetic-SCID mice, or activated spc enriched in specific cell
subpopulations demonstrated that CD4+, CD8+,
and NK cells are all needed to mediate the full anti-angiogenetic
effect of IL-12.
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