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Mol Ther ; 30(2): 644-661, 2022 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-34547462


Preclinical and clinical studies have validated the antitumor effects of several oncolytic viruses (OVs). However, the efficacy of OVs is limited when they are administered as monotherapies. Combination therapy is a promising direction for oncolytic virotherapy in the future. A high dose of vitamin C (VitC) exerts anticancer effects by triggering the accretion of substantial amounts of reactive oxygen species (ROS). OVs can induce immunogenic tumor cell death and elicit an antitumor immune response. ROS play an important role in immunogenic cell death (ICD). This study aimed to explore whether high-dose VitC in combination with oncolytic adenoviruses (oAds) exhibited a synergistic antitumor effect. High-dose VitC synergized with oAds against tumor by enhancing immunogenic tumor cell death. Combination therapy with high-dose VitC and oAds significantly increased the number of T cells in the tumor microenvironment (TME) and promoted the activation of T cells. Furthermore, the antitumor effect of the combination therapy was CD8+ T cell dependent. In addition, combination therapy with high-dose VitC and oAds reprogramed the immunosuppressive TME. Our study provides a new strategy for combination therapy of OVs.

Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos , Adenoviridae/genética , Humanos , Muerte Celular Inmunogénica , Neoplasias/terapia , Virus Oncolíticos/fisiología , Microambiente Tumoral
J Biol Chem ; 278(24): 21831-6, 2003 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-12651849


Angiogenesis is important for the growth of solid tumors. The breaking of the immune tolerance against the molecule associated with angiogenesis should be a useful approach for cancer therapy. However, the immunity to self-molecules is difficult to elicit by a vaccine based on autologous or syngeneic molecules due to immune tolerance. Basic fibroblast growth factor (bFGF) is a specific and potent angiogenic factor implicated in tumor growth. The biological activity of bFGF is mediated through interaction with its high-affinity receptor, fibroblast growth factor receptor-1 (FGFR-1). In this study, we selected Xenopus FGFR-1 as a model antigen by the breaking of immune tolerance to explore the feasibility of cancer therapy in murine tumor models. We show here that vaccination with Xenopus FGFR-1 (pxFR1) is effective at antitumor immunity in three murine models. FGFR-1-specific autoantibodies in sera of pxFR1-immunized mice could be found in Western blotting analysis. The purified immunoglobulins were effective at the inhibition of endothelial cell proliferation in vitro and at the antitumor activity in vivo. The antitumor activity and production of FGFR-1-specific autoantibodies could be abrogated by depletion of CD4+ T lymphocytes. Histological examination revealed that the autoantibody was deposited on the endothelial cells within tumor tissues from pxFR1-immunized mice, and intratumoral angiogenesis was significantly suppressed. Furthermore, the inhibition of angiogenesis could also be found in alginate-encapsulate tumor cell assay. These observations may provide a new vaccine strategy for cancer therapy through the induction of autoimmunity against FGFR-1 associated with angiogenesis in a cross-reaction.

Vacunas contra el Cáncer , Neoplasias/prevención & control , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Alginatos/química , Animales , Antineoplásicos/farmacología , Western Blotting , Linfocitos T CD4-Positivos/metabolismo , División Celular , Clonación Molecular , ADN Complementario/metabolismo , Relación Dosis-Respuesta a Droga , Endotelio Vascular/química , Endotelio Vascular/inmunología , Ensayo de Inmunoadsorción Enzimática , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Inmunoglobulinas/química , Ratones , Trasplante de Neoplasias , Neoplasias/tratamiento farmacológico , Neovascularización Patológica , Plásmidos/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Factores de Tiempo , Transfección , Células Tumorales Cultivadas , Xenopus