Endogenous IL-12 triggers an antiangiogenic program in melanoma cells

doi:10.1073/pnas.0609028104

Endogenous IL-12 triggers an antiangiogenic program in melanoma cells

*Laboratory of Oncology, G. Gaslini Institute, 16147 Genoa, Italy;
^‡Department of Oncology and Neurosciences, “G. d'Annunzio” University and Ce.S.I. Aging Research Center, “G. d'Annunzio” University Foundation, 66013 Chieti, Italy;
^§Animal Model Facility, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy;
^¶Laboratory of Experimental Immnunology, National Cancer Institute-Center for Cancer Research, Frederick, MD 21702-1201; and
^‖Department of Human Anatomy and Histology, University of Bari, 70124 Bari, Italy

Edited by Ralph M. Steinman, The Rockefeller University, New York, NY, and approved January 3, 2007 (received for review October 12, 2006)

Abstract

The IL12RB2 gene acts as a tumor suppressor in human B cell malignancies. Indeed, Il12rb2 knockout (KO) mice develop spontaneously B cell tumors, but also lung epithelial tumors. This latter phenotype may be related to (i) impairment of host IL-12-mediated immunosurveillance and/or (ii) IL-12 inability to inhibit directly the growth of IL-12 unresponsive malignant cells. To address this issue, we transplanted IL-12R⁺ B16 melanoma cells into syngeneic Il12rb2 KO mice with the following rationale: (i) these mice have severe defects in IFN-γ production, as well as in cytotoxic T lymphocyte and natural killer cell cytotoxicity, and (ii) they produce but do not use IL-12 that can potentially bind to and target tumor cells only. Il12rb2 KO mice displayed higher endogenous serum levels of IL-12 and developed smaller B16 tumors than WT animals. These tumors showed reduced proliferation, increased apoptosis, and defective microvessel formation related to down-regulated expression of a set of proangiogenic genes previously unrelated to IL-12. Such effects depended on direct activity of endogenous IL-12 on tumor cells in KO mice, and hydrodynamic delivered IL-12 caused further reduced tumorigenicity of B16 cells in these mice. A previously undescribed mechanism of the IL-12 antitumor activity has been here identified and characterized.

Footnotes

^†To whom correspondence should be addressed at:
Laboratory of Oncology, G. Gaslini Institute, Largo G. Gaslini 5, 16148 Genova, Italy.
E-mail: irmaairoldi{at}ospedale-gaslini.ge.it
Author contributions: V.P. designed research; I.A., E.D.C., C.C., G.T., T.D., E.O., and D.R. performed research; M.W. contributed new reagents/analytic tools; I.A., E.D.C., and V.P. analyzed data; and I.A. and V.P. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
Abbreviations:

Th,

T helper;

PCNA,

proliferating cell nuclear antigen;

CAM,

chorioallantoic membrane;

NK,

natural killer;

KO,

knockout;

α-sma,

α-smooth muscle actin;

CTL,

cytotoxic T lymphocyte.