Abstract
Tumor microenvironment is extremely immunosuppressive, preventing efficient induction of antitumor immunity. To overcome tumor-mediated immunosuppression and enhance the potency of immunogene therapy, oncolytic adenovirus (Ad) co-expressing interleukin (IL)-12 and vascular endothelial growth factor (VEGF)-specific short hairpin ribonucleic acid (shVEGF; RdB/IL12/shVEGF) was generated. Intratumoral injection of RdB/IL12/shVEGF induced a strong antitumor effect in an immune competent B16-F10 melanoma model. RdB/IL12/shVEGF restored immune surveillance function in tumor tissues and actively recruited immune cells by elevating the expression levels of IL-12 and interferon-γ. RdB/IL12/shVEGF efficiently suppressed expression of immunosuppressive VEGF, resulting in restoration of the antitumor immune response and prevention of thymic atrophy. In situ delivery of RdB/IL12/shVEGF to tumor tissues resulted in massive infiltration of differentiated CD4+ T cells, CD8+ T cells, natural killer cells, and dendritic cells to tissues surrounding the necrotic region of tumor. Furthermore, RdB/IL12/shVEGF induced a potent tumor-specific T helper type 1 immune response, implying that attenuation of the immunosuppressive environment mediated by downregulation of VEGF can significantly enhance immune stimulatory functions in the tumor milieu. Collectively, these findings indicate the potential of inducing and restoring potent antitumor immunity using intratumorally administered oncolytic Ad co-expressing IL-12 and shVEGF.
Highlights
The field of cancer immunology and immunotherapy has been an important focus of basic and clinical research since early discoveries of tumor antigens and adaptive immunity [1,2,3]
We demonstrate that the enhanced antitumor effect was associated with increased IFN-γ expression, induction of a tumor-specific immune response, recruitment of immune cells (CD4+, CD8+ T cells, dendritic cells (DCs), and natural killer (NK) cells), and efficient prevention of tumor-induced thymic atrophy
To examine oncolytic Ad-mediated expression of IL-12 and downregulation of vascular endothelial growth factor (VEGF), B16-F10 melanoma cells were infected with RdB, RdB/shVEGF, RdB/IL12, or RdB/IL12/shVEGF
Summary
The field of cancer immunology and immunotherapy has been an important focus of basic and clinical research since early discoveries of tumor antigens and adaptive immunity [1,2,3]. Downregulation of immune function in cancer patients with clinically apparent tumors has been reported, resulting in poor disease management by immunotherapeutics [5]. The success of cancer immunotherapy is critically reliant on correction of the immunosuppressive tumor microenvironment and subsequent restoration of antitumor immune function. IL-12 has been shown to elicit potent antitumor activity in a number of in vivo murine tumor models by inducing an immunomodulatory effect [8,9,10,11,12,13,14,15]. Clinical benefits of systemically administered IL-12 recombinant protein are limited by its dose-limiting side effects, poor half-life, and insufficient accumulation at tumor tissues [15,16,17,18]
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