title: IFN-gamma-inducible protein-10 is essential for the generation of a protective tumor-specific CD8 T cell response induced by single-chain IL-12 gene therapy.
abstract: 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-gamma-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-gamma 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.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: U
authors.initials: U
authors.lastname: Pertl
authors.forename: A D
authors.initials: AD
authors.lastname: Luster
authors.forename: N M
authors.initials: NM
authors.lastname: Varki
authors.forename: D
authors.initials: D
authors.lastname: Homann
authors.forename: G
authors.initials: G
authors.lastname: Gaedicke
authors.forename: R A
authors.initials: RA
authors.lastname: Reisfeld
authors.forename: H N
authors.initials: HN
authors.lastname: Lode
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000502:physiology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D018664:Interleukin-12 / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D016513:Mice, SCID; D009447:Neuroblastoma / Q000098:blood supply / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000637:transplantation; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology
chemical_list: D020533:Angiogenesis Inhibitors; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D018984:Epitopes, T-Lymphocyte; D019444:Vaccines, DNA; D018664:Interleukin-12