Author ORCID Identifier

https://orcid.org/0000-0002-7211-4176

Date of Graduation

8-2021

Document Type

Dissertation (PhD)

Program Affiliation

Experimental Therapeutics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Juan Fueyo, M.D., F.A.A.N.

Committee Member

Chantale Bernatchez, Ph.D.

Committee Member

Krishna Bhat, Ph.D.

Committee Member

Joya Chandra, Ph.D.

Committee Member

Jason Huse, M.D./Ph.D.

Committee Member

Ji Young Yoo, Ph.D.

Abstract

Glioblastoma is the most common malignant primary brain tumor in adults; the current aggressive treatment results in a 5% five-year survival rate. More effective therapies should be developed. One promising alternative is oncolytic adenovirus, Delta-24-RGD, which elicits cancer cell lysis and immunogenic cell death. In fact, Delta-24-RGD produced complete responses in 20% of recurrent glioblastoma patients through immune mechanisms that activate anti-tumor cytotoxic properties of T-cells. This cytolytic effect can further be enhanced by adding immune agonists, namely OX40L, which engages the OX40 receptor to co-stimulate activated T cells for enhanced proliferation. Hence, we produced the next generation of Delta-24-RGD, called Delta-24-RGDOX, which expresses OX40L. Our previous publications exhibited enhanced immune-activating responses and improved survival in glioma-bearing mice treated with Delta-24-RGDOX compared to Delta-24-RGD. Nevertheless, maximal survival of glioma-bearing mice is unattainable, suggesting the presence of sustained immunosuppression within the glioma microenvironment. For example, indoleamine-2,3-dioxygenase (IDO) is upregulated in glioblastoma, correlates with poor prognoses, and is a main source of immunosuppression. IDO is an IFN inducible enzyme that catabolizes tryptophan resulting in diminished proliferation or apoptosis of surrounding effector T cells. Furthermore, kynurenine (Kyn), a tryptophan metabolite, induces T-cell differentiation into Tregs. Excess Kyn also activates carcinogenic transcription factor, aryl hydrocarbon receptor (AhR), which further mediates lymphocyte dysfunction and immunosuppression. Relating to our studies, the immune stimulating effect of Delta-24-RGDOX triggers IFN production contributing to a positive IDO-Kyn-AhR feedback loop. Additionally, IDO-mediated tryptophan depletion hinders viral replication. Therefore, we hypothesized that combining Delta-24-RGDOX with IDO inhibitors will improve therapeutic outcomes and enhance antitumor immune responses of murine glioblastoma. Here, we showed that Delta-24-RGDOX activated the IDO-Kyn-AhR cascade in glioma cells. Furthermore, we demonstrated enhanced therapeutic effectiveness of combined IDO inhibitor and Delta-24-RGDOX treatment compared to single agents, which was validated in immunocompetent IDO-KO mice. The combination treatment efficacy required CD4+ T cell activation and associated with increased activation of T cells and decreased Tregs and MDSCs. This microenvironment remodeling correlated with complete tumor elimination. Altogether, Delta-24-RGDOX activates the IDO-Kyn-AhR cascade, identifying new targets, which when inhibited have the potential to enhance anti-glioma effects of oncolytic-viruses by reversing tumor immunosuppression.

Keywords

oncolytic viruses, glioma, IDO, OX40, tumor microenvironment

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