title: Depletion of myeloid-derived suppressor cells during interleukin-12 immunogene therapy does not confer a survival advantage in experimental malignant glioma.
abstract: Myeloid-derived suppressor cells (MDSCs) accumulate in the glioma microenvironment during tumor progression and promote immunosuppression. Interleukin-12 (IL-12) immunogene therapy can alter MDSCs toward an antigen-presenting cell phenotype and these mature cells can have a central role in antigen presentation. It remains unclear, however, how MDSC depletion can affect glioma immunotherapy. In this study, we generated a replication-deficient adenoviral vector, Ad.5/3.cRGD-mIL12p70, that transduces the GL261-based murine glioma cell line, resulting in the induction of biologically active, murine IL12p70 expression. Ex vivo, IL-12 expressed by GL261 cells induced interferon-γ synthesis in CD8(+) T cells (P<0.001), CD4(+) T cells (P=0.009) and natural killer cells (P=0.036). When injected 1 week after tumor implantation, Ad.5/3.cRGD-mIL12p70 successfully prolonged the survival of glioma-bearing mice. Sixty percent of animals treated with IL-12 immunotherapy were long-term survivors over 175 days, whereas all the control group animals expired by 40 days after tumor implantation (P=0.026). Mice receiving Ad.5/3.cRGD-mIL12p70 also accumulated 50% less MDSCs in the brain than the control group (P=0.007). Moreover, in the IL-12 group, MDSCs significantly overexpressed CD80 and major histocompatibility complex class II molecules (P=0.041). Depletion of MDSCs with Gr1(+) antibody had no survival benefit induced by IL-12-mediated immunotherapy. Of note, IL-12 therapy increased the presence of myeloid dendritic cells (mDCs) in the glioma microenvironment (P=0.0069). Ultimately, the data show that in the context of IL-12 immunogene therapy, MDSCs are dispensable and mDCs may provide the majority of antigen presentation in the brain.
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
authors.forename: B
authors.initials: B
authors.lastname: Thaci
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
authors.forename: A U
authors.initials: AU
authors.lastname: Ahmed
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
authors.forename: I V
authors.initials: IV
authors.lastname: Ulasov
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Wainwright
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
authors.forename: P
authors.initials: P
authors.lastname: Nigam
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
authors.forename: B
authors.initials: B
authors.lastname: Auffinger
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Tobias
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Han
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 1] The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA [2] Department of Neurosurgery, Chonnam National University Hwasun Hospital and Medical School, Jeollanam-do, Korea.
authors.forename: K-S
authors.initials: KS
authors.lastname: Moon
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Lesniak
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D001932:Brain Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D005910:Glioma / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D007167:Immunotherapy; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology*
chemical_list: D018664:Interleukin-12