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.

Simian Immunodeficiency Virus-Producing Cells in Follicles Are Partially Suppressed by CD8+CellsIn Vivo

“…Interleukin-15 (IL-15) is a cytokine that facilitates CD8 ϩ and CD4 ϩ effector T cell expansion while having no preferential effect on the proliferation of Tregs (67). In addition, IL-27 delivery inhibits CD4 ϩ CD25 ϩ Foxp3 ϩ Treg expansion and potentiates tumor-specific CTL reactivity (68). Based on these properties, it is reasonable to speculate that therapeutic IL-15 and IL-27 administration might lead to lower levels of Tregs and higher levels of effector T cells in lymphoid tissues, and thus lead to improved viral control.…”

IL-27, a Cytokine, and IFN-λ1, a Type III IFN, Are Coordinated To Regulate Virus Replication through Type I IFN

“…IL-27 is a heterodimeric anti-inflammatory cytokine composed of EBI3 and p28, which regulates Th cell function during autoimmune and pathogen-induced immune responses (1,3,4). IL-27 exhibits various therapeutic capabilities, such as regulating antiviral ability (12,13), enhancing antitumor immune responses (14), directing antiproliferative effects on tumors (15)(16)(17), and reducing the inflammation associated with experimental autoimmune arthritis (18,19). Serum IL-27 triggers an earlier immune response to prevent hepatic injury in different clinical-pathologic stages of HBV-infected patients (50).…”

“…Overexpressing IL-27 decreases regulatory T cell frequencies, induces spontaneous inflammation, and activates proliferation of naive human B cells and CD4 + T cells (10,11). IL-27 has therapeutic potential through various mechanisms: inhibiting replication of HIV (12) and hepatitis C virus (HCV) (13), enhancing antitumor immune responses (14), directing antiproliferative effects on tumors (15)(16)(17), and reducing the inflammation associated with experimental autoimmune arthritis (18,19). We recently demonstrated that during influenza A virus (IAV) infection, IL-27 is strongly induced through cyclooxygenase-2 (COX-2)-and protein kinase A (PKA)-signaling pathways (20).…”

Fenretinide sensitizes multidrug-resistant human neuroblastoma cells to antibody-independent and ch14.18-mediated NK cell cytotoxicity

“…Cytokines such as interleukin-2 (IL-2), IL-12 [36], and IL-27 [37] either as a single agent or in combination have demonstrated antitumor efficacy in preclinical neuroblastoma models.…”