title: Immunologic and therapeutic synergy of IL-27 and IL-2: enhancement of T cell sensitization, tumor-specific CTL reactivity and complete regression of disseminated neuroblastoma metastases in the liver and bone marrow.
abstract: IL-27 exerts antitumor activity in murine orthotopic neuroblastoma, but only partial antitumor effect in disseminated disease. This study demonstrates that combined treatment with IL-2 and IL-27 induces potent antitumor activity in disseminated neuroblastoma metastasis. Complete durable tumor regression was achieved in 90% of mice bearing metastatic TBJ-IL-27 tumors treated with IL-2 compared with only 40% of mice bearing TBJ-IL-27 tumors alone and 0% of mice bearing TBJ-FLAG tumors with or without IL-2 treatment. Comparable antitumor effects were achieved by IL-27 protein produced upon hydrodynamic IL-27 plasmid DNA delivery when combined with IL-2. Although delivery of IL-27 alone, or in combination with IL-2, mediated pronounced regression of neuroblastoma metastases in the liver, combined delivery of IL-27 and IL-2 was far more effective than IL-27 alone against bone marrow metastases. Combined exposure to IL-27 produced by tumor and IL-2 synergistically enhances the generation of tumor-specific CTL reactivity. Potentiation of CTL reactivity by IL-27 occurs via mechanisms that appear to be engaged during both the initial sensitization and effector phase. Potent immunologic memory responses are generated in mice cured of their disseminated disease by combined delivery of IL-27 and IL-2, and depletion of CD8(+) ablates the antitumor efficacy of this combination. Moreover, IL-27 delivery can inhibit the expansion of CD4(+)CD25(+)Foxp3(+) regulatory and IL-17-expressing CD4(+) cells that are otherwise observed among tumor-infiltrating lymphocytes from mice treated with IL-2. These studies demonstrate that IL-27 and IL-2 synergistically induce complete tumor regression and long-term survival in mice bearing widely metastatic neuroblastoma tumors.
authors.affiliation: Science Applications International Corporation, National Cancer Institute-Frederick, MD 21702, USA. lmirosi@ncifcrf.gov
authors.forename: Rosalba
authors.initials: R
authors.lastname: Salcedo
authors.forename: Julie A
authors.initials: JA
authors.lastname: Hixon
authors.forename: Jimmy K
authors.initials: JK
authors.lastname: Stauffer
authors.forename: Rashmi
authors.initials: R
authors.lastname: Jalah
authors.forename: Alan D
authors.initials: AD
authors.lastname: Brooks
authors.forename: Tahira
authors.initials: T
authors.lastname: Khan
authors.forename: Ren-Ming
authors.initials: RM
authors.lastname: Dai
authors.forename: Loretta
authors.initials: L
authors.lastname: Scheetz
authors.forename: Erin
authors.initials: E
authors.lastname: Lincoln
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Back
authors.forename: Douglas
authors.initials: D
authors.lastname: Powell
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hurwitz
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sayers
authors.forename: Robert
authors.initials: R
authors.lastname: Kastelein
authors.forename: George N
authors.initials: GN
authors.lastname: Pavlakis
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Felber
authors.forename: Giorgio
authors.initials: G
authors.lastname: Trinchieri
authors.forename: Jon M
authors.initials: JM
authors.lastname: Wigginton
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000276:immunology* / Q000494:pharmacology; D019046:Bone Marrow Neoplasms / Q000188:drug therapy / Q000556:secondary; D004357:Drug Synergism; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000008:administration & dosage / Q000276:immunology*; D007378:Interleukins / Q000008:administration & dosage / Q000276:immunology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy / Q000276:immunology* / Q000556:secondary; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
chemical_list: C486767:Il27 protein, mouse; D007376:Interleukin-2; D007378:Interleukins; D007371:Interferon-gamma