The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma

Minghui Li; Aaron R Bolduc; Md Nasrul Hoda; Denise N Gamble; Sarah-Bianca Dolisca; Anna K Bolduc; Kelly Hoang; Claire Ashley; David McCall; Amyn M Rojiani; Bernard L Maria; Olivier Rixe; Tobey J MacDonald; Peter S Heeger; Andrew L Mellor; David H Munn; Theodore S Johnson

doi:10.1186/2051-1426-2-21

The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma

J Immunother Cancer. 2014 Jul 7:2:21. doi: 10.1186/2051-1426-2-21. eCollection 2014.

Authors

Minghui Li¹, Aaron R Bolduc², Md Nasrul Hoda³, Denise N Gamble⁴, Sarah-Bianca Dolisca⁵, Anna K Bolduc⁴, Kelly Hoang⁵, Claire Ashley⁵, David McCall⁴, Amyn M Rojiani⁶, Bernard L Maria⁷, Olivier Rixe⁸, Tobey J MacDonald⁹, Peter S Heeger¹⁰, Andrew L Mellor¹¹, David H Munn¹, Theodore S Johnson¹

Affiliations

¹ 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.
² 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.
³ 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.
⁴ GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Program in Cancer immunology, Inflammation and Tolerance (CIT), Georgia Regents University, Augusta, GA, USA.
⁵ Medical College of Georgia Department of Pediatrics, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA CN-4141A, USA.
⁶ GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Department of Pathology, Georgia Regents University, Augusta, GA, USA.
⁷ 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.
⁸ GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Department of Medicine, Georgia Regents University, Augusta, GA, USA.
⁹ Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322, USA.
¹⁰ 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.
¹¹ 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.

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.

Keywords: Chemotherapy; Complement; Glioblastoma; IDO; Immunotherapy; Indoleamine; Indoximod; NLG919; Radiation therapy; Tumor.

Abstract

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