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Remodeling of Tumor Immune Microenvironment by Oncolytic Viruses.

ABSTRACT: Oncolytic viruses (OVs) are potential antitumor agents with unique therapeutic mechanisms. They possess the ability of direct oncolysis and the induction of antitumor immunity. OV can be genetically engineered to potentiate antitumor efficacy by remodeling the tumor immune microenvironment. The present mini review mainly describes the effect of OVs on remodeling of the tumor immune microenvironment and explores the mechanism of regulation of the host immune system and the promotion of the immune cells to destroy carcinoma cells by OVs. Furthermore, this article focuses on the utilization of OVs as vectors for the delivery of immunomodulatory cytokines or antibodies.

SUBMITTER: Zhang B

PROVIDER: S-EPMC7934618 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Remodeling of Tumor Immune Microenvironment by Oncolytic Viruses.

Zhang Bin B Wang Xilei X Cheng Ping P

Frontiers in oncology 20210219

Oncolytic viruses (OVs) are potential antitumor agents with unique therapeutic mechanisms. They possess the ability of direct oncolysis and the induction of antitumor immunity. OV can be genetically engineered to potentiate antitumor efficacy by remodeling the tumor immune microenvironment. The present mini review mainly describes the effect of OVs on remodeling of the tumor immune microenvironment and explores the mechanism of regulation of the host immune system and the promotion of the immune ...[more]

PMID: 33680911

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Project description:BackgroundOncolytic viruses are considered part of immunotherapy and have shown promise in preclinical experiments and clinical trials. Results from these studies have suggested that tumor microenvironment remodeling is required to achieve an effective response in solid tumors. Here, we assess the extent to which targeting specific mechanisms underlying the immunosuppressive tumor microenvironment optimizes viroimmunotherapy.MethodsWe used RNA-seq analyses to analyze the transcriptome, and validated the results using Q-PCR, flow cytometry, and immunofluorescence. Viral activity was analyzed by replication assays and viral titration. Kyn and Trp metabolite levels were quantified using liquid chromatography-mass spectrometry. Aryl hydrocarbon receptor (AhR) activation was analyzed by examination of promoter activity. Therapeutic efficacy was assessed by tumor histopathology and survival in syngeneic murine models of gliomas, including Indoleamine 2,3-dioxygenase (IDO)-/- mice. Flow cytometry was used for immunophenotyping and quantification of cell populations. Immune activation was examined in co-cultures of immune and cancer cells. T-cell depletion was used to identify the role played by specific cell populations. Rechallenge experiments were performed to identify the development of anti-tumor memory.ResultsBulk RNA-seq analyses showed the activation of the immunosuppressive IDO-kynurenine-AhR circuitry in response to Delta-24-RGDOX infection of tumors. To overcome the effect of this pivotal pathway, we combined Delta-24-RGDOX with clinically relevant IDO inhibitors. The combination therapy increased the frequency of CD8+ T cells and decreased the rate of myeloid-derived suppressor cell and immunosupressive Treg tumor populations in animal models of solid tumors. Functional studies demonstrated that IDO-blockade-dependent activation of immune cells against tumor antigens could be reversed by the oncometabolite kynurenine. The concurrent targeting of the effectors and suppressors of the tumor immune landscape significantly prolonged the survival in animal models of orthotopic gliomas.ConclusionsOur data identified for the first time the in vivo role of IDO-dependent immunosuppressive pathways in the resistance of solid tumors to oncolytic adenoviruses. Specifically, the IDO-Kyn-AhR activity was responsible for the resurface of local immunosuppression and resistance to therapy, which was ablated through IDO inhibition. Our data indicate that combined molecular and immune therapy may improve outcomes in human gliomas and other cancers treated with virotherapy.

Dataset Information

Remodeling of Tumor Immune Microenvironment by Oncolytic Viruses.

Publications

Remodeling of Tumor Immune Microenvironment by Oncolytic Viruses.

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