title: Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma.
abstract: Adaptive immune resistance in the tumor microenvironment appears to attenuate the immunotherapeutic targeting of glioblastoma (GBM). In this study, we identified a tumor-infiltrating myeloid cell (TIM) population that expands in response to dendritic cell (DC) vaccine treatment. The aim of this study was to understand how this programmed death ligand 1 (PD-L1)-expressing population restricts activation and tumor-cytolytic function of vaccine-induced tumor-infiltrating lymphocytes (TILs).
  
  
  
  To test this hypothesis in our in vivo preclinical model, we treated mice bearing intracranial gliomas with DC vaccination ± murine anti-PD-1 monoclonal antibody (mAb) blockade or a colony stimulating factor 1 receptor inhibitor (CSF-1Ri) (PLX3397) and measured overall survival. We then harvested and characterized the PD-L1+ TIM population and its role in TIL activation and tumor cytolysis in vitro.
  
  
  
  Our data indicated that the majority of PD-L1 expression in the GBM environment is contributed by TIMs rather than by tumor cells themselves. While PD-1 blockade partially reversed the TIL dysfunction, targeting TIMs directly with CSF-1Ri altered TIM expression of key chemotactic factors associated with promoting increased TIL infiltration after vaccination. Neither PD-1 mAb nor CSF-1Ri had a demonstrable therapeutic benefit alone, but when combined with DC vaccination, a significant survival benefit was observed. When the tripartite regimen was given (DC vaccine, PD-1 mAb, PLX3397), long-term survival was noted together with an increase in the number of TILs and TIL activation.
  
  
  
  Together, these studies elucidate the role that TIMs play in mediating adaptive immune resistance in the GBM microenvironment and provide evidence that they can be manipulated pharmacologically with agents that are clinically available. Development of immune resistance in response to active vaccination in GBM can be reversed with dual administration of CSF-1Ri and PD-1 mAb.
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Antonios
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors.forename: Horacio
authors.initials: H
authors.lastname: Soto
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Everson
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Moughon
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors.forename: Joey R
authors.initials: JR
authors.lastname: Orpilla
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors.forename: Namjo P
authors.initials: NP
authors.lastname: Shin
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors.forename: Shaina
authors.initials: S
authors.lastname: Sedighim
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Treger
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Odesa
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tucker
authors.affiliation: Department of Pathology and Laboratory Medicine,  David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.affiliation: Department of Biostatistics,  David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Brain Research Institute,  David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.|Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.|Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.|Brain Research Institute,  David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.|Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Liau
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.|Brain Research Institute,  David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.|Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.|Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Prins
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage*; D005260:Female; D005909:Glioblastoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D019496:Cancer Vaccines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: CSF-1R; PD-1; cancer; checkpoint inhibitors; dendritic cell vaccine; glioblastoma; immunotherapy