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Immunotherapy of tumors with recombinant adenovirus encoding macrophage inflammatory protein 3beta induces tumor-specific immune response in immunocompetent tumor-bearing mice.

ABSTRACT: AIM: Tumor immunotherapy aims at activating the body's own immune system to fight an existing tumor. Effective antitumor responses require tumor antigens to be presented to lymphocytes. We aimed to test the hypothesis that intratumoral administration of recombinant adenovirus encoding MIP3beta would induce antitumor immunity by attracting and facilitating the interaction between lymphocytes and dendritic cells. METHODS: A recombinant adenovirus encoding microphage inflammatory protein 3beta (AdMIP3beta) was constructed. The antitumor activity of AdMIP3beta in BALB/c and C57BL/6 mice bearing CT26 colon adenocarcinoma and Lewis lung cancer was evaluated. RESULTS: Immunotherapy with AdMIP3beta resulted in significant inhibition of tumor growth and prolonged survival of tumor-bearing mice. Tumor-specific immune responses elicited by AdMIP3beta include MHC class I-dependent CD8(+) CTL-mediated immune response and IFN-gamma response. Immunohistochemical staining demonstrated numerous CD11c(+) cells and CD3(+) T lymphocytes within tumor tissues of AdMIP3beta-treated mice. These findings suggest that the mechanism of specific antitumor immunity induced by AdMIP3beta may be involved in the chemoattraction of both T lymphocytes and DCs to the tumor site and thus facilitate the process of antigen capture and mature DC to prime naive T cells. CONCLUSION: The present study may be important in the exploration of the potential application of AdMIP3beta in the treatment of a broad spectrum of tumors.

SUBMITTER: Hou JM

PROVIDER: S-EPMC4002396 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Immunotherapy of tumors with recombinant adenovirus encoding macrophage inflammatory protein 3beta induces tumor-specific immune response in immunocompetent tumor-bearing mice.

Hou Jian-mei JM Zhao Xia X Tian Ling L Li Gang G Zhang Ru R Yao Bing B Deng Hong-xin HX Yang Jin-liang JL Wei Yu-quan YQ

Acta pharmacologica Sinica 20090301 3

<h4>Aim</h4>Tumor immunotherapy aims at activating the body's own immune system to fight an existing tumor. Effective antitumor responses require tumor antigens to be presented to lymphocytes. We aimed to test the hypothesis that intratumoral administration of recombinant adenovirus encoding MIP3beta would induce antitumor immunity by attracting and facilitating the interaction between lymphocytes and dendritic cells.<h4>Methods</h4>A recombinant adenovirus encoding microphage inflammatory prote ...[more]

PMID: 19262559

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Project description:BACKGROUND:Gene therapy using a recombinant adenovirus (Ad) encoding secretory human endostatin (Ad-Endo) has been demonstrated to be a promising antiangiogenesis and antitumor strategy of in animal models and clinical trials. The E1B55KD-deficient Ad dl1520 was also found to replicate selectively in and destroy cancer cells. In this study, we aimed to investigate the antitumor effects of antiangiogenic agent Ad-Endo combined with the oncolytic Ad dl1520 on gastric cancer (GC) in vitro and in vivo and determine the mechanisms of these effects. METHODS:The Ad DNA copy number was determined by real-time PCR, and gene expression was assessed by ELISA, Western blotting or immunohistochemistry. The anti-proliferation effect (cytotoxicity) of Ad was assessed using the colorimetry-based MTT cell viability assay. The antitumor effects were evaluated in BALB/c nude mice carrying SGC-7901 GC xenografts. The microvessel density and Ad replication in tumor tissue were evaluated by checking the expression of CD34 and hexon proteins, respectively. RESULTS:dl1520 replicated selectively in GC cells harboring an abnormal p53 pathway, including p53 mutation and the loss of p14(ARF) expression, but did not in normal epithelial cells. In cultured GC cells, dl1520 rescued Ad-Endo replication, and dramatically promoted endostatin expression by Ad-Endo in a dose- and time-dependent manner. In turn, the addition of Ad-Endo enhanced the inhibitory effect of dl1520 on the proliferation of GC cells. The transgenic expression of Ad5 E1A and E1B19K simulated the rescue effect of dl1520 supporting Ad-Endo replication in GC cells. In the nude mouse xenograft model, the combined treatment with dl1520 and Ad-Endo significantly inhibited tumor angiogenesis and the growth of GC xenografts through the increased endostatin expression and oncolytic effects. CONCLUSIONS:Ad-Endo combined with dl1520 has more antitumor efficacy against GC than Ad-Endo or dl1520 alone. These findings indicate that the combination of Ad-mediated antiangiogenic gene therapy and oncolytic Ad therapeutics could be one of promising comprehensive treatment strategies for GC.

Project description:Virus-like particles (VLPs) have been gaining attention as potential platforms for delivery of cargos in nanomedicine. Although animal viruses are largely selected due to their immunostimulatory capacities, VLPs from plant viruses constitute a promising alternative to be considered. VLPs derived from Turnip mosaic virus (TuMV) have proven to present a tridimensional structure suited to display molecules of interest on their surface, making them interesting tools to be studied in theragnostic strategies. Here, we study their potential in the treatment of food allergy by genetically coupling TuMV-derived VLPs to Pru p 3, one of the most dominant allergens in Mediterranean climates. VLPs-Pru p 3 were generated by cloning a synthetic gene encoding the TuMV coat protein and Pru p 3, separated by a linker, into a transient high-expression vector, followed by agroinfiltration in Nicotiana benthamiana plants. The generated fusion protein self-assembled in planta to form the VLPs, which were purified by exclusion chromatography. Their elongated morphology was confirmed by electron microscopy and their size (~400 nm), and monodispersity was confirmed by dynamic light scattering. Initial in vitro characterization confirmed that they were able to induce proliferation of human immune cells. This proliferative capability was enhanced when coupled with the natural lipid ligand of Pru p 3. The resultant formulation, called VLP-Complex, was also able to be transported by intestinal epithelial cells, without affecting the monolayer integrity. In light of all these results, VLP-Complex was furtherly tested in a mouse model of food allergy. Sublingual administration of VLP-Complex could effectively reduce some serological markers associated with allergic responses in mice, such as anti-Pru p 3 sIgE and sIgG2a. Noteworthy, no associated macroscopic, nephritic, or hepatic toxicity was detected, as assessed by weight, blood urea nitrogen (BUN) and galectin-3 analyses, respectively. Our results highlight the standardized production of allergen-coated TuMV-VLPs in N. benthamiana plants. The resulting formula exerts notable immunomodulatory properties without the need for potentially hazardous adjuvants. Accordingly, no detectable toxicity associated to their administration was detected. As a result, we propose them as good candidates to be furtherly studied in the treatment of immune-based pathologies.

Project description:Abstract INTRODUCTION We recently demonstrated that hematopoietic stem and progenitor cell (HSC) transfer during adoptive T cell immunotherapy (ACT) for malignant brain tumors facilitates extended survival and long-term cures. HSCs migrated to tumors and used T cell-released IFN-g to differentiate into dendritic cells (DCs). In those studies, we transferred syngeneic HSCs from naïve hosts that were not endemic to the tumor-bearing hosts, unlike the clinical paradigm of autologous transfers. In peripheral cancers, HSCs of tumor-bearing hosts (TB HSCs) possess considerable immunosuppressive potential. OBJECTIVE We therefore evaluated the immunologic function of HSCs from naïve and tumor-bearing hosts to determine if malignant gliomas affect the immune-potentiating function of HSCs. METHODS We used treatment-resistant intracranial gliomas KR158B and GL261 to generate TB HSCs that were isolated from the bone marrow. We then performed in vitro HSC culture experiments alone and with activated T cell supernatants to study HSC differentiation by flow cytometry. Intravenous transfers were used to study HSC differentiation in brain tumors as well as survival benefit during ACT. RESULTS Culturing naïve or TB HSCs led to differentiation into 30% or 60% myeloid-derived suppressor cells (MDSCs; CD11b+Ly-6G/6C+), respectively. However, when cultured in activated T cell supernatants containing IFN-g, both HSC types differentiated into 30% MDSCs and 80% MHCII+ antigen-presenting cells. We then determined that TB HSCs express more IFN-gR than naïve HSCs including 40% more IFN-gR1 and 90% more IFN-gR2 on DC progenitors. In vivo, ACT rescued intratumoral TB HSC differentiation, prolonged median survival, and led to long-term cures. CONCLUSIONS While gliomas exert an immunosuppressive pressure on TB HSCs, ACT can reprogram TB HSC differentiation into functional antigen-presenting cells. A phase I trial evaluating the impact of HSC transfer on adoptive immunotherapy in pediatric high-grade gliomas is underway at our center (ACTION; clinicaltrials.gov NCT03334305).

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Immunotherapy of tumors with recombinant adenovirus encoding macrophage inflammatory protein 3beta induces tumor-specific immune response in immunocompetent tumor-bearing mice.

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Immunotherapy of tumors with recombinant adenovirus encoding macrophage inflammatory protein 3beta induces tumor-specific immune response in immunocompetent tumor-bearing mice.

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