Synergistic antileukemia effect of combinational gene therapy using murine b-defensin 2 and IL-18 in L1210 murine leukemia model

Abstract

Murine b-defensin 2 (MBD2) is not only chemotactic for immature dendritic cells but also activates them by Toll-like receptor 4. We have previously demonstrated that vaccine with MBD2 elicited potent antileukemia responses in the L1210 murine model. Interleukin-18 (IL-18) is an essential cytokine for the generation of Th1 response and natural killer cells and cytotoxic T lymphocytes (CTL) activation. As MBD2 and IL-18 appear to function on different components required by an effective antitumor immune response including both innate and adaptive immunity, we investigated whether combinatorial delivery of MBD2 and IL-18 transduced L1210 cells could elicit synergistic antileukemia effects. First, we constructed a single plasmid vector carrying both pro-IL-18 and IL-1b converting enzyme (ICE) genes, and found that transfection of this vector into L1210 cells resulted in efficient secretion of bioactive IL-18. Combinatorial delivery of MBD2 and pro-IL-18-ICE modified L1210 cells conferred a superior inhibition of leukemogenicity over either L1210-MBD2 or L1210-pro-IL-18-ICE alone; moreover, the survived mice developed long-lasting protective immunity as determined by rechallenge experiments. This combined vaccine also elicited the most marked therapeutic effect, CTL activity and interferon-g production. These results suggest that the combination of MBD2 and IL-18 induces more effective antileukemia activity and provides a promising strategy for cancer therapy.

β-defensin 2 as an Adjuvant Promotes Anti-Melanoma Immune Responses and Inhibits the Growth of Implanted Murine Melanoma In Vivo

“…IFN-γ is predominately secreted by activated Th1, CD8 + T cells, and NK cells while IL-12 is produced by activated antigen presenting cells. Conceivably, vaccination with B16-mBD2 induces pro-inflammatory Th1, CD8 + T cells, and activates NK cells, consistent with previous findings [11], [17]. As a result, the activated immunocompetent cells may migrate into the tumor tissues, inhibiting the growth of implanted melanoma in mice.…”

“…β-defensin 2 is an antimicrobial peptide and can regulate immune response [8]. Previous studies have shown that vaccination with plasmids for the fused protein of β-defensin 2 and tumor antigen or with β-defensin 2-expressing irradiated tumor cells stimulates strong antitumor immune responses against lymphoma, leukemia, and mammary adenocarcinoma in vivo [10], [11], [17], [18]. In this study, we determined whether β-defensin 2 could act as an adjuvant to induce melanoma-specific T cell immunity in mice.…”

Distinct Effects of IL-18 on the Engraftment and Function of Human Effector CD8+ T Cells and Regulatory T Cells

“…For example, IL-18 enhances the efficacy of DNA vaccines directed against prostate-specific antigen [14] or Fos-related antigen [15]. Additionally, IL-18 augments the efficacy of DC-based vaccines [16], [17] as well as whole-cell tumor vaccines [18]. However, IL-18 has also been reported to enhance tumor progression (reviewed in [19]).…”

Inflammasomes and Cancer: The Dynamic Role of the Inflammasome in Tumor Development

“…On the other hand, the immunomodulatory of inflammasome activities, particularly IL-18, can be harnessed for immunotherapy against cancer. IL-18 has been shown to play an important role in the induction of IFNγ production, increasing NK cell activity and T cell proliferation ( 135 – 140 ). Notably, those immunoregulatory activities of IL-18 are overlapped with that of IL-12.…”