Abstract
Simple SummaryInterleukin (IL) 15 is a proinflammatory cytokine and is well-known as an efficacious cytokine for cancer immunotherapy. Interestingly, the IL-15:IL-15Rα complex, a self-assembling form of IL-15 and its soluble receptor α (IL-15Rα), has shown greater antitumor activity than IL-15 itself. However, the development of a suitable multigene delivery system is needed for further applications of IL-15:IL-15Rα. Baculovirus, an arthropod-specific virus, is known for its adjuvant effect in cancer therapy. Here, we investigated the potential of the BacMam virus, a modified baculovirus for gene delivery into mammalian cells, as a novel multigene delivery system to generate a cell-based cancer vaccine secreting the self-assembling IL-15:IL-15Rα complex. Vaccination with a BacMam-based IL-15:IL-15Rα cancer vaccine triggered antitumor immune responses in a tumor antigen-specific manner. Our findings indicate that the BacMam system is a safe and effective method to produce protective and therapeutic cancer vaccines.This study reports the use of the BacMam system to deliver and express self-assembling IL-15 and IL-15Rα genes to murine B16F10 melanoma and CT26 colon cancer cells. BacMam-based IL-15 and IL-15Rα were well-expressed and assembled to form the biologically functional IL-15:IL-15Rα complex. Immunization with this IL-15:IL-15Rα cancer vaccine delayed tumor growth in mice by inducing effector memory CD4+ and CD8+ cells and effector NK cells which are tumor-infiltrating. It caused strong antitumor immune responses of CD8+ effector cells in a tumor-antigen specific manner both in vitro and in vivo and significantly attenuated Treg cells which a control virus-infected cancer vaccine could induce. Post-treatment with this cancer vaccine after a live cancer cell injection also prominently delayed the growth of the tumor. Collectively, we demonstrate a vaccine platform consisting of BacMam virus-infected B16F10 or CT26 cancer cells that secrete IL-15:IL-15Rα. This study is the first demonstration of a functionally competent soluble IL-15:IL-15Rα complex-related cancer vaccine using a baculovirus system and advocates that the BacMam system can be used as a secure and rapid method of producing a protective and therapeutic cancer vaccine.
Highlights
This article is an open access articleInterleukin (IL) 15 is a member of the cytokine family that all utilize the common gamma-chain receptor which includes IL-2, IL-4, IL-7, IL-9, and IL-21
We showed that the IL-2 signal sequence (IL-2ss) facilitated the assembly and secretion of IL-15 and IL-15Rα as a complex when it was used instead of the self-signal sequence of IL-15 or IL-15Rα [3]
The selfassembling IL-15:IL-15Rα complex contained two subunit proteins (IL-15 and IL-15Rα) which were guided to intracellular assembly by the IL-2 signal peptide
Summary
Interleukin (IL) 15 is a member of the cytokine family that all utilize the common gamma-chain (γc ) receptor which includes IL-2, IL-4, IL-7, IL-9, and IL-21. IL-15 is functionally the closest cytokine to IL-2 as they share the heterodimeric IL-2/IL-15Rβγ receptor complex to deliver their signals. Unlike IL-2, the specificity and biological activity of IL-15 depends mainly on its private receptor chain IL-15Rα [1,2]. The development, activation, survival, and cytotoxic function of T cells and NK cells. IL-15 has attracted attention for its promising antitumor effects. Many studies have attempted to exploit the antitumor potential of IL-15 as an immunotherapeutic agent for the treatment of various types of cancer and used a number of different approaches
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