title: Intratumoral oncolytic adenoviral treatment modulates the glioma microenvironment and facilitates systemic tumor-antigen-specific T cell therapy.
abstract: Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor and is associated with poor survival. Virotherapy is a promising candidate for the development of effective, novel treatments for GBM. Recent studies have underscored the potential of virotherapy in enhancing antitumor immunity despite the fact that its mechanisms remain largely unknown. Here, using a syngeneic GBM mouse model, we report that intratumoral virotherapy significantly modulates the tumor microenvironment. We found that intratumoral administration of an oncolytic adenovirus, AdCMVdelta24, decreased tumor-infiltrating CD4+Foxp3+regulatory T cells (Tregs) and increased IFNγ-producing CD8+T cells in treated tumors, even in late stage disease in which a highly immunosuppressive tumor microenvironment is considered to be a significant barrier to immunotherapy. Importantly, intratumoral AdCMVdelta24 treatment augmented systemically transferred tumor-antigen-specific T cell therapy. Furthermore, mechanistic studies showed (1) downregulation of Foxp3 in Tregs that were incubated with media conditioned by virus-infected tumor cells, (2) downregulation of indoleamine 2,3 dioxygenase 1 (IDO) in glioma cells upon infection by AdCMVdelta24, and (3) reprograming of Tregs from an immunosuppressive to a stimulatory state. Taken together, our findings demonstrate the potency of intratumoral oncolytic adenoviral treatment in enhancing antitumor immunity through the regulation of multiple aspects of immune suppression in the context of glioma, supporting further clinical development of oncolytic adenovirus-based immune therapies for malignant brain cancer.
authors.affiliation: The Brain Tumor Center; Pritzker School of Medicine; The University of Chicago ; Chicago, IL USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Qiao
authors.affiliation: The Brain Tumor Center; Pritzker School of Medicine; The University of Chicago ; Chicago, IL USA.
authors.forename: Mahua
authors.initials: M
authors.lastname: Dey
authors.affiliation: The Brain Tumor Center; Pritzker School of Medicine; The University of Chicago ; Chicago, IL USA.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Chang
authors.affiliation: The Brain Tumor Center; Pritzker School of Medicine; The University of Chicago ; Chicago, IL USA.
authors.forename: Julius W
authors.initials: JW
authors.lastname: Kim
authors.affiliation: The Brain Tumor Center; Pritzker School of Medicine; The University of Chicago ; Chicago, IL USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Miska
authors.affiliation: The Brain Tumor Center; Pritzker School of Medicine; The University of Chicago ; Chicago, IL USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Ling
authors.affiliation: Oncolytic Adenovirus Group; German Cancer Research Center (DKFZ) ; Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: M Nettlebeck
authors.affiliation: The Brain Tumor Center; Pritzker School of Medicine; The University of Chicago ; Chicago, IL USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.affiliation: The Brain Tumor Center; Pritzker School of Medicine; The University of Chicago ; Chicago, IL USA.
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The Brain Tumor Center; Pritzker School of Medicine; The University of Chicago ; Chicago, IL USA.
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
keywords: Tregs; glioblastoma; immunosuppression; immunotherapy; oncolytic adenovirus; regulatory T cells; tumor microenvironment; virotherapy