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-Inducible Protein-10 Is Essential for the Generation of a Protective Tumor-Specific CD8 T Cell Response Induced by Single-Chain IL-12 Gene Therapy1
*
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037;
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129;
University of California, Cancer Center 0961, La Jolla, CA 92093; and
Charité Children’s Hospital, Berlin, Germany
The successful induction of T cell-mediated protective immunity
against poorly immunogenic malignancies remains a major challenge for
cancer immunotherapy. Here, we demonstrate that the induction of
tumor-protective immunity by IL-12 in a murine neuroblastoma model
depends entirely on the CXC chemokine IFN-
-inducible protein 10
(IP-10). This was established by in vivo depletion of IP-10 with mAbs
in mice vaccinated against NXS2 neuroblastoma by gene therapy with a
linearized, single-chain (sc) version of the heterodimeric cytokine
IL-12 (scIL-12). The efficacy of IP-10 depletion was indicated by the
effective abrogation of scIL-12-mediated antiangiogenesis and T cell
chemotaxis in mice receiving s.c. injections of scIL-12-producing NXS2
cells. These findings were extended by data demonstrating that IP-10 is
directly involved in the generation of a tumor-protective
CD8+ T cell-mediated immune response during the early
immunization phase. Four lines of evidence support this contention:
First, A/J mice vaccinated with NXS2 scIL-12 and depleted of IP-10 by
two different anti-IP-10 mAbs revealed an abrogation of
systemic-protective immunity against disseminated metastases. Second,
CD8+ T cell-mediated MHC class I Ag-restricted tumor cell
lysis was inhibited in such mice. Third, intracellular IFN-
expressed by proliferating CD8+ T cells was substantially
inhibited in IP-10-depleted, scIL-12 NXS2-vaccinated mice. Fourth,
systemic tumor protective immunity was completely abrogated in mice
depleted of IP-10 in the early immunization phase, but not if IP-10 was
depleted only in the effector phase. These findings suggest that IP-10
plays a crucial role during the early immunization phase in the
induction of immunity against neuroblastoma by scIL-12 gene
therapy.
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