title: The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma.
abstract: BACKGROUND
  Indoleamine 2,3-dioxygenase (IDO) is an enzyme with immune-suppressive properties that is commonly exploited by tumors to evade immune destruction. Anti-tumor T cell responses can be initiated in solid tumors, but are immediately suppressed by compensatory upregulation of immunological checkpoints, including IDO. In addition to these known effects on the adaptive immune system, we previously showed widespread, T cell-dependent complement deposition during allogeneic fetal rejection upon maternal treatment with IDO-blockade. We hypothesized that IDO protects glioblastoma from the full effects of chemo-radiation therapy by preventing vascular activation and complement-dependent tumor destruction.
  
  
  METHODS
  To test this hypothesis, we utilized a syngeneic orthotopic glioblastoma model in which GL261 glioblastoma tumor cells were stereotactically implanted into the right frontal lobes of syngeneic mice. These mice were treated with IDO-blocking drugs in combination with chemotherapy and radiation therapy.
  
  
  RESULTS
  Pharmacologic inhibition of IDO synergized with chemo-radiation therapy to prolong survival in mice bearing intracranial glioblastoma tumors. We now show that pharmacologic or genetic inhibition of IDO allowed chemo-radiation to trigger widespread complement deposition at sites of tumor growth. Chemotherapy treatment alone resulted in collections of perivascular leukocytes within tumors, but no complement deposition. Adding IDO-blockade led to upregulation of VCAM-1 on vascular endothelium within the tumor microenvironment, and further adding radiation in the presence of IDO-blockade led to widespread deposition of complement. Mice genetically deficient in complement component C3 lost all of the synergistic effects of IDO-blockade on chemo-radiation-induced survival.
  
  
  CONCLUSIONS
  Together these findings identify a novel mechanistic link between IDO and complement, and implicate complement as a major downstream effector mechanism for the beneficial effect of IDO-blockade after chemo-radiation therapy. We speculate that this represents a fundamental pathway by which the tumor regulates intratumoral vascular activation and protects itself from immune-mediated tumor destruction.
authors: GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Program in Cancer immunology, Inflammation and Tolerance (CIT), Georgia Regents University, Augusta, GA, USA ; Medical College of Georgia Department of Pediatrics, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA CN-4141A, USA.
authors: Minghui
authors: M
authors: Li
authors: GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Program in Cancer immunology, Inflammation and Tolerance (CIT), Georgia Regents University, Augusta, GA, USA ; Department of Surgery, Georgia Regents University, Augusta, GA, USA.
authors: Aaron R
authors: AR
authors: Bolduc
authors: Department of Neurology, Georgia Regents University, Augusta, GA, USA ; College of Allied Health Sciences Department of Medical Laboratory, Imaging & Radiologic Sciences, Georgia Regents University, Augusta, GA 30912, USA.
authors: Md Nasrul
authors: MN
authors: Hoda
authors: GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Program in Cancer immunology, Inflammation and Tolerance (CIT), Georgia Regents University, Augusta, GA, USA.
authors: Denise N
authors: DN
authors: Gamble
authors: Medical College of Georgia Department of Pediatrics, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA CN-4141A, USA.
authors: Sarah-Bianca
authors: SB
authors: Dolisca
authors: GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Program in Cancer immunology, Inflammation and Tolerance (CIT), Georgia Regents University, Augusta, GA, USA.
authors: Anna K
authors: AK
authors: Bolduc
authors: Medical College of Georgia Department of Pediatrics, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA CN-4141A, USA.
authors: Kelly
authors: K
authors: Hoang
authors: Medical College of Georgia Department of Pediatrics, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA CN-4141A, USA.
authors: Claire
authors: C
authors: Ashley
authors: GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Program in Cancer immunology, Inflammation and Tolerance (CIT), Georgia Regents University, Augusta, GA, USA.
authors: David
authors: D
authors: McCall
authors: GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Department of Pathology, Georgia Regents University, Augusta, GA, USA.
authors: Amyn M
authors: AM
authors: Rojiani
authors: GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Medical College of Georgia Department of Pediatrics, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA CN-4141A, USA ; Department of Neurology, Georgia Regents University, Augusta, GA, USA ; Department of Neurosurgery, Georgia Regents University, Augusta, GA, USA.
authors: Bernard L
authors: BL
authors: Maria
authors: GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Department of Medicine, Georgia Regents University, Augusta, GA, USA.
authors: Olivier
authors: O
authors: Rixe
authors: Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Tobey J
authors: TJ
authors: MacDonald
authors: Department of Medicine, Division of Nephrology, The Immunology Institute, New York, NY 10025, USA ; Recanati-Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10025, USA.
authors: Peter S
authors: PS
authors: Heeger
authors: GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Program in Cancer immunology, Inflammation and Tolerance (CIT), Georgia Regents University, Augusta, GA, USA ; Department of Medicine, Georgia Regents University, Augusta, GA, USA.
authors: Andrew L
authors: AL
authors: Mellor
authors: GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Program in Cancer immunology, Inflammation and Tolerance (CIT), Georgia Regents University, Augusta, GA, USA ; Medical College of Georgia Department of Pediatrics, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA CN-4141A, USA.
authors: David H
authors: DH
authors: Munn
authors: GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Program in Cancer immunology, Inflammation and Tolerance (CIT), Georgia Regents University, Augusta, GA, USA ; Medical College of Georgia Department of Pediatrics, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA CN-4141A, USA.
authors: Theodore S
authors: TS
authors: Johnson
keywords: Chemotherapy; Complement; Glioblastoma; IDO; Immunotherapy; Indoleamine; Indoximod; NLG919; Radiation therapy; Tumor