title: Immunosuppressive Myeloid Cells' Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy.
abstract: Survival of glioma (GBM) patients treated with the current standard of care remains dismal. Immunotherapeutic approaches that harness the cytotoxic and memory potential of the host immune system have shown great benefit in other cancers. GBMs have developed multiple strategies, including the accumulation of myeloid-derived suppressor cells (MDSCs) to induce immunosuppression. It is therefore imperative to develop multipronged approaches when aiming to generate a robust anti-tumor immune response. Herein, we tested whether combining MDSC depletion or checkpoint blockade would augment the efficacy of immune-stimulatory herpes simplex type-I thymidine kinase (TK) plus Fms-like tyrosine kinase ligand (Flt3L)-mediated immune stimulatory gene therapy. Our results show that MDSCs constitute >40% of the tumor-infiltrating immune cells. These cells express IL-4Rα, inducible nitric oxide synthase (iNOS), arginase, programmed death ligand 1 (PDL1), and CD80, molecules that are critically involved in antigen-specific T cell suppression. Depletion of MDSCs strongly enhanced the TK/Flt3L gene therapy-induced tumor-specific CD8 T cell response, which lead to increased median survival and percentage of long-term survivors. Also, combining PDL1 or CTLA-4 immune checkpoint blockade greatly improved the efficacy of TK/Flt3L gene therapy. Our results, therefore, indicate that blocking MDSC-mediated immunosuppression holds great promise for increasing the efficacy of gene therapy-mediated immunotherapies for GBM.
authors.affiliation: Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA; Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA.
authors.forename: Neha
authors.initials: N
authors.lastname: Kamran
authors.affiliation: Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA; Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA.
authors.forename: Padma
authors.initials: P
authors.lastname: Kadiyala
authors.affiliation: Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA; Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA.
authors.forename: Meghna
authors.initials: M
authors.lastname: Saxena
authors.affiliation: Instituto de Investigaciones Biomédicas (CONICET-UBA), Facultad de Medicina, Universidad de Buenos Aires, 1053 Buenos Aires, Argentina.
authors.forename: Marianela
authors.initials: M
authors.lastname: Candolfi
authors.affiliation: Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA; Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA.
authors.forename: Youping
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA; Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA; Instituto de Investigaciones Biomédicas (CONICET-UBA), Facultad de Medicina, Universidad de Buenos Aires, 1053 Buenos Aires, Argentina.
authors.forename: Mariela A
authors.initials: MA
authors.lastname: Moreno-Ayala
authors.affiliation: Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA; Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Raja
authors.affiliation: Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA; Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Shah
authors.affiliation: Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA; Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA.
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Lowenstein
authors.affiliation: Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA; Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA. Electronic address: mariacas@umich.edu.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Castro
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism; D015415:Biomarkers; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D060908:CTLA-4 Antigen / Q000378:metabolism; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005910:Glioma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D006801:Humans; D016130:Immunophenotyping; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology* / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D019076:Transgenes; D059016:Tumor Microenvironment / Q000235:genetics* / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; D015415:Biomarkers; D060908:CTLA-4 Antigen; D008565:Membrane Proteins; C084881:flt3 ligand protein; D013937:Thymidine Kinase
keywords: gene therapy; glioma; immunotherapy; myeloid cells; tumor microenvironment