title: Anti-GITR therapy promotes immunity against malignant glioma in a murine model.
abstract: Regulatory T cells (Tregs) are potently immunosuppressive cells that accumulate within the glioma microenvironment. The reduction in their function and/or trafficking has been previously shown to enhance survival in preclinical models of glioma. Glucocorticoid-induced TNFR-related protein (GITR) is a tumor necrosis factor superfamily receptor enriched on Tregs that has shown promise as a target for immunotherapy. An agonistic antibody against GITR has been demonstrated to inhibit Tregs in a number of models and has only been recently addressed in glioma. In this study, we examined the modality of the antibody function at the tumor site as opposed to the periphery as the blood-brain barrier prevents efficient antibody delivery to brain tumors. Mice harboring established GL261 tumors were treated with anti-GITR monotherapy and were shown to have a significant increase in overall survival (p < 0.01) when antibodies were injected directly into the glioma core, whereas peripheral antibody treatment only had a modest effect. Peripheral treatment resulted in a significant decrease in granzyme B (GrB) expression by Tregs, whereas intratumoral treatment resulted in both a decrease in GrB expression by Tregs and their selective depletion, which was largely mediated by FcγR-mediated destruction. We also discovered that anti-GITR treatment results in the enhanced survival and functionality of dendritic cells (DCs)-a previously unreported effect of this immunotherapy. In effect, this study demonstrates that the targeting of GITR is a feasible and noteworthy treatment option for glioma, but is largely dependent on the anatomical location in which the antibodies are delivered.
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, 676 N St. Clair, Suite 2210, Chicago, IL 60611, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Miska
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, 676 N St. Clair, Suite 2210, Chicago, IL 60611, USA.
authors.forename: Aida
authors.initials: A
authors.lastname: Rashidi
authors.affiliation: Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Chang
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, 676 N St. Clair, Suite 2210, Chicago, IL 60611, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Muroski
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, 676 N St. Clair, Suite 2210, Chicago, IL 60611, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, 676 N St. Clair, Suite 2210, Chicago, IL 60611, USA.
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, 676 N St. Clair, Suite 2210, Chicago, IL 60611, USA.
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005910:Glioma / Q000188:drug therapy*; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
keywords: Dendritic cells; GITR; Glioblastoma multiforme; Immunotherapy; Regulatory T cells