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Ref ID: 345.1 IL-27 mediates complete regression of primary and/or metastatic murine neuroblastoma tumors: role for CD8+ T cells Rosalba Salcedo1, Cynthia Hahn1, Jimmy Stauffer1, Erin Lincoln2, Julie Hixon1, Robert Kastelein3, Jon M. Wigginton1 Pediatric Oncology Branch1, NCI-CCR and IRSP2, SAIC-Frederick, Frederick, MD and Department of Immunology 3, DNAX Research Institute, Palo Alto, CA, USA. We have shown previously that IFN--inducing cytokines such as IL-12 mediate potent antitumor effects against murine neuroblastoma. IL-27 is a newly-described IL-12-related cytokine that triggers clonal expansion of naïve T cells and synergizes with IL-12+/-IL-2 to induce IFNproduction by activated naïve T and/or NK cells. Therefore, we hypothesized that IL-27 might also mediate potent immunoregulatory and therapeutic antitumor activity in vivo. TBJ neuroblastoma cells engineered to overexpress IL-27 demonstrated markedly delayed growth and underwent complete durable regression in over 90% of mice bearing either subcutaneous or orthotopic tumors compared to 15% of control mice. IL-27 expression also mediated complete regression of induced metastatic disease in 40% of mice versus 0% in control mice. IL-27-induced tumor regression occurs in conjunction with local-regional T cell activation. Tumor-draining lymph nodederived lymphocytes from mice bearing subcutaneous TBJ-IL-27 tumors were primed to proliferate more readily when cultured ex vivo with anti-CD3/anti-CD28 compared to those from mice bearing control tumors. Further, potent upregulation of local IFN- gene expression and marked infiltration of CD8+ T cells is observed within TBJ-IL-27 versus control TBJ tumors. Functionally, in vivo depletion of CD8+ but not CD4+ T cells or NK cells abrogates the anti-tumor effects of IL-27. Collectively, these studies demonstrate that IL-27 can enhance immune function in vivo, induce complete regression of both primary and metastatic neuroblastoma tumors via mechanisms that are critically dependent on CD8+ T cells, and suggest that IL-27 could be used to therapeutically potentiate the host antitumor immune response in patients with malignancy.