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1
* Department of Microbiology, State University of New York, Buffalo, NY 14214;
Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912;
Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263; and
Lymphoma Biology Program, Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642
By implanting nondisrupted pieces of human lung tumor biopsy
tissues into SCID mice, it has been possible to establish viable grafts
of the tumor, as well as the tumor-associated microenvironment,
including inflammatory cells, fibroblasts, tumor vasculature, and the
extracellular matrix. Using this xenograft model, we have evaluated and
characterized the effects of a local and sustained release of human
rIL-12 (rhIL-12) from biodegradable microspheres. In response to
rhIL-12, the human CD45+ inflammatory cells present within
the xenograft mediate the suppression or the complete arrest of tumor
growth in SCID mice. Analysis of the cellular events reveals that human
CD4+ and CD8+ T cells are induced by rhIL-12 to
produce and secrete IFN-
. Serum levels of human IFN- in mice
bearing rhIL-12-treated tumor xenografts correlate directly with the
degree of tumor suppression, while neutralizing Abs to human IFN-
abrogate the IL-12-mediated tumor suppression. Gene expression
profiling of tumors responding to intratumoral rhIL-12 demonstrates an
up-regulation of IFN- and IFN--dependent genes not observed in
control-treated tumors. Genes encoding a number of proinflammatory
cytokines, chemokines (and their receptors), adhesion molecules,
activation markers, and the inducible NO synthase are up-regulated
following the introduction of rhIL-12, while genes associated with
tumor growth, angiogenesis, and metastasis are decreased in expression.
NO contributes to the tumor killing because an inhibitor of inducible
NO synthase prevents IL-12-induced tumor suppression. Cell depletion
studies reveal that the IL-12-induced tumor suppression, IFN-
production, and the associated changes in gene expression are all
dependent upon CD4+ T cells.
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